Pyrimidine derivatives

ABSTRACT

wherein (R1)n, R3, R4a, R4b, R5a, R5b and Ar1 are as described in the description and their use in the treatment of cancer by modulating an immune response comprising a reactivation of the immune system in the tumor. The invention further relates to novel benzofurane and benzothiophene derivatives of formula (III) and their use as pharmaceuticals, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as modulators of the prostaglandin 2 receptors EP2 and/or EP4.

The present invention relates to pyrimidine derivatives of formula (I)and their use in the treatment of cancer by modulating an immuneresponse comprising a reactivation of the immune system in the tumor.The present invention further relates to novel pyrimidine derivatives offormula (III) and their use as pharmaceuticals. The invention alsoconcerns related aspects including processes for the preparation of thecompounds, pharmaceutical compositions containing one or more compoundsof formula (I)/formula (III), and their use as modulators of the PGE2receptors EP2 (alias PTGER2, alias PGE2 Receptor EP2 Subtype) and/or EP4(alias PTGER4, alias EP4R, alias PGE2 Receptor EP4 Subtype). Thecompounds of formula (I)/formula (III) may especially be used as singleagents or in combination with one or more therapeutic agents and/orchemotherapy and/or radiotherapy and/or immunotherapy in theprevention/prophylaxis or treatment of cancers; in particular theprevention/prophylaxis or treatment of melanoma; lung cancer; bladdercancer; renal carcinomas; gastro-intestinal cancers; endometrial cancer;ovarian cancer; cervical cancer; and neuroblastoma.

Prostaglandin E2 (PGE2) is a bioactive lipid that can elicit a widerange of biological effects associated with inflammation and cancer.PGE2 belongs to the prostanoid family of lipids. Cyclooxygenase (COX) isthe rate-limiting enzyme in the synthesis of biological mediators termedprostanoids, consisting of prostaglandin PGD2, PGE2, PGF2a, prostacyclinPGI2, and thromboxane TXA2. Prostanoids function via activation of seventransmembrane G-protein-coupled receptors (GPCRs), in particular EP1,EP2, EP3, and EP4 are receptors for PGE2. Activation of both EP2 and EP4by PGE2 stimulates adenylate cyclase, resulting in elevation ofcytoplasmic cAMP levels to initiate multiple downstream events via itsprototypical effector Protein kinase A. In addition, PGE2 is also ableto signal via PI3K/AKT and Ras-MAPK/ERK signalling

Cancers figure among the leading causes of death worldwide. Tumors arecomprised of abnormally proliferating malignant cancer cells but also ofa functionally supportive microenvironment. This tumor microenvironmentis comprised of a complex array of cells, extracellular matrixcomponents, and signaling molecules and is established by the alteredcommunication between stromal and tumor cells. As tumors expand in size,they elicit the production of diverse factors that can help the tumor togrow such as angiogenic factors (promoting ingrowth of blood vessels) orthat can help to evade the attack of the host immune response. PGE2 issuch an immuno-modulatory factor produced in tumors.

It is well established that COX2, mainly via PGE2, promotes overallgrowth of tumors and is upregulated and correlates with clinical outcomein a high percentage of common cancers, especially colorectal, gastric,esophageal, pancreatic, breast and ovarian cancer. High COX-2 and PGE2expression levels are associated with neoplastic transformation, cellgrowth, angiogenesis, invasiveness, metastasis and immune evasion.

The finding that COX2 is over-expressed and plays an important role incarcinogenesis in gastrointestinal (GI) cancers including among othersesophagus, gastric and colorectal cancers has led to the fact thatCOX-inhibitors (Coxibs), including Celecoxib, and other nonsteroidalanti-inflammatory drugs (NSAID), including aspirin, are among the moststudied cancer chemopreventive agents in development today (for reviewsee for example Wang R et al, Curr Pharm Des. 2013; 19(1):115-25; GarciaRodriguez L A et al, Recent Results Cancer Res. 2013; 191:67-93, Sahin IH et al, Cancer Lett. 2014 Apr. 10; 345(2):249-57; Drew D A et al, NatRev Cancer 2016, 16:173; Brotons C et al, Am J Cardiovasc Drugs. 2015April; 15(2):113)

In addition to COX2 and PGE2, also EP receptors, especially EP2 and EP4,are aberrantly over-expressed in multiple types of cancers, especiallyin gastro-intestinal (GI) cancers and pancreatic cancer. Furthermore,the over-expression of PGE2 and/or EP2 and/or EP4 correlates withdiseases progression in some cancer types such as oesophageal squamouscell carcinoma (Kuo K T et al, Ann Surg Onc 2009; 16(2), 352-60);squamous cell carcinoma of the lung (Alaa M et al, Int J Oncol 2009,34(3); 805-12); prostate cancer (Miyata Y et al, Urology 2013,81(1):136-42); Badawi A F and Badr M Z Int J Cancer. 2003,103(1):84-90); head and neck squamous cell carcinoma (Gallo O et al, HumPathol. 2002, 33(7):708-14).

In accordance to studies performed with Coxibs, in mice, knockout ofeither COX1, COX2, microsomal prostaglandin E synthase 1 (mPTGES1), EP2or EP4 resulted in reduced tumor incidence and progression in differenttumor models. Conversely, overexpression of COX2 or mPTGES1 intransgenic mice resulted in increased tumor incidence and tumor burden(for review see Nakanishi M. and Rosenberg D. W., Seminars inImmunopathology 2013, 35: 123-137; Fischer S M et al Cancer Prev Res(Phila) 2011 November; 4(11):1728-35; Fulton A M et al Cancer Res 2006;66(20); 9794-97).

Several pharmacological studies to inhibit tumor growth and progressionusing EP receptor antagonists or COX2 inhibitors in different tumormodels have been conducted in mice. Among others, EP antagonists and/orCOX2 inhibitors reduced tumor growth and metastasis in experimentalmodels of colorectal cancer (e.g Yang L et al Cancer Res 2006, 66(19),9665-9672; Pozzi A. et al JBC 279(28); 29797-29804), lung carcinomas(Sharma S et al Cancer Res 2005 65(12), 5211-5220), gastro-intestinalcancer (Oshima H et al Gastroenterology 2011, 140(2); 596-607; Fu S L etal world J Gastroenterol 2004, 10(13); 1971-1974), breast cancer (KunduN et al, Breast Cancer Res Treat 117, 2009; 235-242; Ma X et al,Oncolmmunology 2013; Xin X et al Lab Investigation 2012, 1-14; MarkosyanN et al; Breast Cancer Res 2013, 15:R75), prostate cancer (Xu S et al,Cell Biochem Biophys 2014, Terada et al Cancer Res 70(4) 2010;1606-1615), pancreatic cancer (Al-Wadei H A et al, PLOS One 2012,7(8):e43376; Funahashi H et al, Cancer Res 2007, 67(15):7068-71). COX2inhibitors were approved for the treatment of familial adenomatouspolyposis (FAP) which is an inherited pre-disposition syndrome forcolorectal cancer, but later retracted due to cardiovascular sideeffects.

Mechanistically, PGE2 signalling is mainly involved in the crosstalkbetween tumor and stromal cells, thereby creating a microenvironmentwhich is favourable for the tumor to grow. In particular, PGE2signalling via EP2 and EP4 can for example (i) suppress the cytotoxicityand cytokine production of natural killer cells, (ii) skew thepolarization of tumor-associated macrophages towards tumor-promoting M2macrophages (see for example Nakanishi Y et al Carcinogenesis 2011,32:1333-39), (iii) regulate the activation, expansion and effectorfunction of both Tregs (regulatory T cells) and MDSC (myeloid derivedsuppressor cells), which are potent immunosuppressive cells thataccumulate in tumors both in patients and in experimental animal models(see for example Sharma S et al, Cancer Res 2005, 5(12):5211-20; Sinha Pet al Cancer Res 2007, 67(9), 4507-4513; Obermajer N et al, Blood 2011,118(20):5498-5505); (iv) down-regulate IFN-γ, TNF-α IL-12 and IL-2expression in immune cells such as natural killer cells, T-cells,dendritic cells and macrophages, impairing the ability of these immunecells to induce tumor cell apoptosis and restrain tumorigenesis (see forexample Bao Y S et al, Int Immunopharmacol. 2011; 11(10):1599-605; Kim JG and Hahn Y S, Immunol Invest. 2000; 29(3):257-69; Demeuere C E et al,Eur J Immunol. 1997; 27(12):3526-31; Mitsuhashi M et al, J Leukoc Biol.2004; 76(2):322-32; Pockaj B A et al, Ann Surg Oncol. 2004;11(3):328-39; (v) suppress activation, IL-2 responsiveness, expansionand cytotoxicity of T-cells thereby contributing to localimmunsuppresion (see for example Specht C et al, Int J Cancer200191:705-712); (vi) inhibit maturation of dendritic cells, theirability to present antigens and to produce IL-12, resulting in abortiveactivation of cytotoxic T-cells (see for example Ahmadi M et al, CancerRes 2008, 68(18):7250-9; Stolina M et al, J Immunol 2000, 164:361-70);(vii) regulate tumor angiogenesis (formation of new blood vessels fornutrient and oxygen supply) by enhancing endothelial cell motility andsurvival as well as by increasing the expression of VEGF (vascularendothelial growth factor) (see for example Zhang Y and Daaka Y, Blood2011; 118(19):5355-64; Jain S et al, Cancer Res. 2008; 68(19):7750-9;Wang and Klein, Molecular Carcinogenesis 2007, 46:912-923; (viii)enhance tumor cell survival (via PI3K/AKT and MAPK signalling). Forreview see for example Kalinski P, J Immunol 2012, 188(1), 21-28;Obermajer N et al, Oncoimmunology 1(5), 762-4; Greenhough A et al,carcinogenesis 2009, 30(3), 377-86; Wang D and Dubois R N, Gut 2006, 55,115-122; Harris S G e al Trends Immunol 2002, 22, 144-150).

Coxibs have been shown to render tumor cells more sensitive to radiationand chemotherapy and several clinical trials have been performed or areongoing combining Coxibs with radio- and/or chemotherapy (for review seee.g Ghosh N et al, Pharmacol Rep. 2010 March-April; 62(2):233-44; DavisT W et al, Am J Clin Oncol. 2003, 26(4):558-61; see also Higgins J P etal, Cancer Biol Ther 2009, 8:1440-49).

Furthermore, there is some evidence of additive effects and/or synergybetween Coxibs and epidermal growth factor receptor (EGFR) inhibitors(see for example Zhang X et al, Clin Cancer Res. 2005, 11(17):6261-9;Yamaguchi N H et al, J Gastrointest Oncol. 2014, 5(1):57-66); and witharomatase inhibitors (see for example Generali D et al, Br J Cancer.2014; 111(1):46-54; Lustberg M B et all, Clin Breast Cancer. 2011August; 11(4):221-7; Falandry C et al, Breast Cancer Res Treat. 2009August; 116(3):501-8); Chow L W et al, J Steroid Biochem Mol Biol. 2008,111(1-2):13-7).

Moreover, additive/synergistic effects have been seen in different mousetumor models when Aspirin (a COX1/2 inhibitor) was combined with andanti-VEGF antibody (Motz G T et al; Nat Med 2014 20(6):607) and thiscombination is currently under investigation in clinical trials(NCT02659384).

Recently, it has been shown that, if combined, differentimmunotherapeutic approaches can have enhanced anti-tumor efficacy. Dueto the immune-modulatory properties of PGE2, Coxibs have thus also beenused in combination with different immunotherapeutic approaches. Inparticular, additive or even synergistic effects could be observed whenCoxibs were combined with dendritic cell vaccination in a rat gliomamodel and in a mouse mesothelioma or melanoma model (Zhang H et al,Oncol Res. 2013; 20(10):447-55; Veltman J D et al, BMC Cancer. 2010;10:464; Toomey D et all, Vaccine. 2008 Jun. 25; 26(27-28):3540-9); withgranulocyte-macrophage colony-stimulating factor (GM-CSF) in mouse braintumors (Eberstål S et al, Int J Cancer. 2014 Jun. 1; 134(11):2748-53);with interferon gamma (IFN-γ) in brain tumors (Eberstål S et al, CancerImmunol Immunother. 2012, 61(8):1191-9); with dendritic cell vaccinationor with GM-CSF in a mouse breast cancer model (Hahn T et al, Int JCancer. 2006, 118(9):2220-31); and with adenoviral interferon beta(IFN−) therapy in a mouse mesothelioma model (DeLong P et al, CancerRes. 2003 Nov. 15; 63(22):7845-52). Along these lines, additive or evensynergistic effects of Coxibs and/or EP2 and/or EP4 antagonists can alsobe envisaged with agents acting on cytotoxic T-lymphocyte-associatedprotein 4 (CTLA-4) such as anti-CTLA-4 antibodies; anti-TIM-3antibodies, anti-Lag-3 antibodies; anti-TIGIT antibodies; or, inparticular, with agents acting on programmed cell death protein 1 (PD1),such as anti-PD1 or anti-PDL1 (programmed cell death ligand 1)antibodies (Yongkui Li et al Oncoimmunology 2016, 5(2):e1074374; ZelenayS et al, Cell 2015, 162; 1-14; WO2013/090552, which indicates asynergistic effect of dual EP2 and EP4 blockade in combination withagents acting on PD1).

Adenosine is another endogenous factor with anti-inflammatory propertiesthat is generated through the activity of ectonucleotidases, CD39 andCD73, expressed on various cell types, including regulatory T cells(Treg) (Mandapathil M et al, J Biol Chem. 2010; 285(10):7176-86). Immunecells also respond to Adenosine, because they bear receptors for ADO,which are mainly of the A2a/A2b type (Hoskin D W, et al, Int J Oncol2008, 32:527-535). Signaling via Adenosine receptors and EP2/EP4receptors converges on the cytoplasmic adenylyl cyclase, leading toup-regulation of cAMP. It was shown that Adenosine and PGE2 cooperate inthe suppression of immune responses mediated by regulatory T cells(Mandapathil M et al, J Biol Chem. 2010; 285(36):27571-80; Caiazzo E etal, Biochem Pharmacol. 2016; 112:72-81).

Thus, the present EP2 and/or EP4 antagonists may be useful, alone, or incombination with one or more therapeutic agents and/or chemotherapyand/or radiotherapy and/or immunotherapy; in particular in combinationwith chemotherapy, radiotherapy, EGFR inhibitors, aromatase inhibitors,anti-angiogenic drugs, adenosine inhibitors, immunotherapy such asespecially PD1 and/or PDL1 blockade, or other targeted therapies; forthe prevention/prophylaxis or treatment of cancers, notably for theprevention/prophylaxis or treatment of skin cancer including melanomaincluding metastatic melanoma; lung cancer including non-small cell lungcancer; bladder cancer including urinary bladder cancer, urothelial cellcarcinoma; renal carcinomas including renal cell carcinoma, metastaticrenal cell carcinoma, metastatic renal clear cell carcinoma;gastro-intestinal cancers including colorectal cancer, metastaticcolorectal cancer, familial adenomatous polyposis (FAP), oesophagealcancer, gastric cancer, gallbladder cancer, cholangiocarcinoma,hepatocellular carcinoma, and pancreatic cancer such as pancreaticadenocarcinoma or pancreatic ductal carcinoma; endometrial cancer;ovarian cancer; cervical cancer; neuroblastoma; prostate cancerincluding castrate-resistant prostate cancer; brain tumors includingbrain metastases, malignant gliomas, glioblastoma multiforme,medulloblastoma, meningiomas; breast cancer including triple negativebreast carcinoma; oral tumors; nasopharyngeal tumors; thoracic cancer;head and neck cancer; leukemias including acute myeloid leukemia, adultT-cell leukemia; carcinomas; adenocarcinomas; thyroid carcinomaincluding papillary thyroid carcinoma; choriocarcinoma; Ewing's sarcoma;osteosarcoma; rhabdomyosarcoma; Kaposi's sarcoma; lymphoma includingBurkitt's lymphoma, Hodgkin's lymphoma, MALT lymphoma; multiplemyelomas; and virally induced tumors.

In addition, selective or dual EP2 and/or EP4 antagonists may be usefulin several other diseases or disorders responding for example totreatment with COX2 inhibitors, with the advantage that EP2 and/or EP4antagonists should not possess the potential cardiovascular side effectsseen with COX2 inhibitors, which are mainly due to interference withPGI2 and TXA2 synthesis (see for example Boyd M J et al, bioorganic andmedicinal chemistry letters 21, 484, 2011). For example, blockade ofprostaglandin production by COX inhibitors is the treatment of choicefor pain, including especially inflammatory pain and painfulmenstruation. Thus EP2 and/or EP4 and/or dual EP2/EP4 antagonists may beuseful for the treatment of pain, especially inflammatory pain. Evidencefrom EP2 knockout mice suggest that EP2 antagonists can be used for thetreatment of inflammatory hyperalgesia (Reinold H et al, J Clin Invest2005, 115(3):673-9). In addition, EP4 antagonists have beneficial effectin vivo in inflammatory pain models (eg Murase A, Eur J Pharmacol 2008;Clark P, J Pharmacol Exp Ther. 2008; Maubach K A Br J Pharmacol. 2009;Colucci J Bioorg Med Chem Lett. 2010, Boyd M J et al, Bioorg Med ChemLett 2011, Chn Q et al Br J Phramacol 2010, Nakao K et al, J PharmacolExp Ther. 2007 August; 322(2):686-94). Administration of an EP2 incombination with an EP4 antagonist showed significant, but partialinhibition of joint inflammation in mouse collagen-induced arthritismodel (Honda T et al J Exp Med 2006, 203(2):325-35).

EP2 and/or dual EP2/EP4 antagonists may be of use to decrease femalefertility, i.e. they have been shown to prevent pregnancy if used ascontraceptive in macaques (Peluffo M C et al Hum Reprod 2014). EP2knockout mice have decreased fertility, smaller litter sizes and reducedcumulus expansion (Matsumoto et al, Biology of reproduction 2001, 64;1557-65; Hitzaki et al, PNAS 1999, 96(18), 10501-10506; Tilley S L JClin Inves 1999, 103(11):1539-45; Kennedy C R et al, Nat Med 19995(2):217-20).

There is also rationale that EP2 and/or EP4 antagonists may be of use toprevent or treat endometriosis: for example EP2, EP3 and EP4 and COX2are overexpressed in endometriosis cell lines and tissues (e.g. SantulliP et al J Clin Endocrinol Metab 2014, 99(3):881-90); antagonisttreatment was shown to inhibit the adhesion of endometrial cells invitro (Lee J et al Biol Reprod 2013, 88(3):77; Lee J et al Fertil Steril201, 93(8):2498-506); COX2 inhibitors have been shown to reduceendometric lesions in mice via EP2 (Chuang P C et al, Am J Pathol 2010,176(2):850-60); and antagonist treatment has been shown to induceapoptosis of endometric cells in vitro (Banu S K et al, MOI endocrinol2009, 23(8) 1291-305).

Dual EP2/EP4 antagonists, or the combination of a selective EP2antagonists with a selective EP4 antagonist, may be of potential use forautoimmune disorders; e.g. they have been shown to be effective in mousemodel for multiple sclerosis (MS) (Esaki Y et al PNAS 2010,107(27):12233-8; Schiffmann S et al, Biochem Pharmacol. 2014, 87(4):625-35; see also Kofler D M et al J Clin Invest 2014, 124(6):2513-22).Activation of EP2/EP4 signalling in cells in vitro (Kojima F et alProstaglandins Other Lipid Mediat 2009, 89:26-33) linked dual orselective EP2 and/or EP4 antagonists to the treatment of rheumatoidarthritis. Also, elevated levels of PGE(2) have been reported insynovial fluid and cartilage from patients with osteoarthritis (OA) andit has been shown that PGE2 stimulates matrix degradation inosteoarthitis chondrocytes via the EP4 receptor (Attur M et al, JImmunol. 2008; 181(7):5082-8).

EP4 overexpression is associated with enhanced inflammatory reaction inatherosclerotic plaques of patients (Cipollone F et al, ArtheriosclerThromb Vasc Biol 2005, 25(9); 1925-31), thus the use of EP4 and/or dualEP2/EP4 antagonists may be indicated for plaque stabilization andprevention/prophylaxis of acute ischemic syndromes. In addition, EP4deficiency suppresses early atherosclerosis, by compromising macrophagesurvival (Babaev V R et al, Cell Metab. 2008 December; 8(6):492-501) EP2and/or dual EP2/EP4 antagonists may also be useful in the treatment ofpneumonia: intrapulmonary administration of apoptotic cells demonstratedthat PGE(2) via EP2 accounts for subsequent impairment of lungrecruitment of leukocytes and clearance of Streptococcus pneumoniae, aswell as enhanced generation of IL-10 in vivo (Medeiros Al et al J ExpMed 2009 206(1):61-8).

EP2 and/or dual EP2/EP4 antagonists may in addition be useful for thetreatment of neurodegenerative diseases (for review see Cimino P J etal, Curr Med Chem. 2008; 15(19):1863-9). EP2 receptor acceleratesprogression of inflammation in a mouse model of amyotrophic lateralsclerosis (ALS) (Liang X et al, Ann Neurol 2008, 64(3):304-14); COX2inhibitors have been shown to be neuroprotective in rodent models ofstroke, Parkinson disease and ALS (for review see Liang X et al J MolNeurosci 2007, 33(1):94-9), decreased neurotoxicity was observed in EP2knockout mice treated with parkinsonian toxican (Jin J et al, JNeuroinflammation 2007, 4:2), PGE2 via EP2 aggravates neurodegenerationin cultured rat cells (Takadera T et al, Life Sci 2006, 78(16):1878-83); Reduced amyloid burden was observed in Alzheimer's diseasemouse model if crossed with EP2 knockout mice (Liang X et al J Neurosci2005, 25(44):10180-7; Keene C D et al, Am J Pathol. 2010,177(1):346-54). EP2 null mice are protected from CD14-dependent/innateimmunity mediated neuronal damage in neurodegenerative disease (Shie F Set al Glia 2005, 52(1):70-7); PGE2 via EP2 increases amyloid precursorprotein (APP) expression in cultured rat microglial cells (Pooler A M etal Neurosci. Lett. 2004, 362(2):127-30). EP2 antagonist limits oxidativedamage from activation of innate immunity (intracranial injection ofLPS) in the brain and could be used for Alzheimer or HIV associateddementia (Montine T J et al, J Neurochem 2002, 83(2):463-70). In anAlzheimer's disease mouse model cognitive function could be improved bygenetic and pharmacological inhibition of EP4 (Hoshino T et al, JNeurochem 2012, 120(5):795-805).

EP2 and/or dual EP2/EP4 antagonists may also be useful to treatautosomal dominant polycystic kidney disease (ADPKD): PGE2 via EP2induces cystogenesis of human renal epithelial cells; and EP2 was foundto be overexpressed in patient samples (Elberg G et al, Am J PhysiolRenal Physiol 2007, 293(5):F1622-32).

EP4 and/or dual EP2/EP4 antagonists may also be useful to treatosteoporosis: PGE2 stimulates bone resorption mainly via EP4 andpartially via EP2 (Suzawa T et all, Endocrinology. 2000 April;141(4):1554-9), EP4 knockout mice show impaired bone resorption (MiyauraC et al, J Biol Chem 2000, 275(26): 19819-23) and an EP4 antagonistsshowed partial inhibition of PGE(2)-stimulated osteoclastogenesis andosteoclastic bone resorption (Tomita M et al, Bone. 2002 January;30(1):159-63).

WO2008/152093 discloses selective EP2 receptor modulators which comprisean indole ring linked to the rest of the molecule in position 3, and apyrimidine moiety which however is not substituted with a directlylinked aromatic substituent. WO2006/044732 discloses pyrimidinecompounds which are modulators of PGD2 claimed to be useful e.g. in thetreatment of allergic diseases; however for example the exemplifiedcompound CAS 1001913-77-4 has been tested to be inactive on both the EP2and the EP4 receptor in the in vitro assay set out in the experimentalpart below. WO2008/006583 discloses pyrimidin derivatives which areALK-5 inhibitors. WO2006/044732 and WO2008/039882 disclose certainpyrimidine derivatives as protaglandin D2 receptor antagonists.Pyrimidin-2-yl derivatives are disclosed in WO2013/020945,WO2012/127032, WO2011/144742, WO2011/022348, WO2009/105220, Bioorg. Med.Chem 2011, 21(13) 4108-4114 and Bioorg. Med. Chem 2011, 21(1) 66-75.Further compounds which are claimed to be active as anti-cancer agentsare disclosed in WO2006/128129, WO2008/008059 and Bioorg. Med. Chem2013, 21(2), 540-546. WO2012/149528 discloses 2-methyl-pyrimidinederivatives as inhibitors of the inducible form ofPhosphofructose-Kinase, thought to useful in the treatment of cancer bydecreasing tumor growth by reducing the extremely high rate ofglycolysis in cancer cells. WO2018/013840, WO2013/163190 WO2015/058067,and WO2015/058031 disclose certain DNA-PK inhibitors interacting withDNA repair processes. The disclosed compounds are thought to be usefulto sensitize cancer cells by directly modulating cancer cellproliferation, and to enhance the efficacy of both cancer chemotherapyand radiotherapy.

The present invention provides novel pyrimidine derivatives of formulae(I), (II), or (III) which are modulators of the prostaglandin 2receptors EP2 and/or EP4. Certain compounds of the present invention aredual antagonists of both the EP2 and the EP4 receptor. The presentcompounds may, thus, be useful for the prevention/prophylaxis ortreatment of diseases which respond to the blockage of the EP2 receptorsand/or the EP4 receptors such as especially cancers, wherein aparticular aspect is the treatment of cancer by modulating an immuneresponse comprising a reactivation of the immune system in the tumor; aswell as pain including especially inflammatory pain and painfulmenstruation; endometriosis; acute ischemic syndromes in atheroscleroticpatients; pneumonia; neurodegenerative diseases including amyotrophiclateral sclerosis, stroke; Parkinson disease, Alzheimer's disease andHIV associated dementia; autosomal dominant polycystic kidney disease;and to control female fertility.

1) A first aspect of the invention relates to compounds of the formula(I)

for use in the treatment of a cancer, wherein said cancer is treated bymodulating an immune response comprising a reactivation of the immunesystem in the tumor;wherein said cancer is notably a cancer selected from melanoma includingmetastatic melanoma; lung cancer including non-small cell lung cancer;bladder cancer including urinary bladder cancer, urothelial cellcarcinoma; renal carcinomas including renal cell carcinoma, metastaticrenal cell carcinoma, metastatic renal clear cell carcinoma;gastro-intestinal cancers including colorectal cancer, metastaticcolorectal cancer, familial adenomatous polyposis (FAP), oesophagealcancer, gastric cancer, gallbladder cancer, cholangiocarcinoma,hepatocellular carcinoma, and pancreatic cancer such as pancreaticadenocarcinoma or pancreatic ductal carcinoma; endometrial cancer;ovarian cancer; cervical cancer; neuroblastoma; prostate cancerincluding castrate-resistant prostate cancer; brain tumors includingbrain metastases, malignant gliomas, glioblastoma multiforme,medulloblastoma, meningiomas; breast cancer including triple negativebreast carcinoma; oral tumors; nasopharyngeal tumors; thoracic cancer;head and neck cancer; leukemias including acute myeloid leukemia, adultT-cell leukemia; carcinomas; adenocarcinomas; thyroid carcinomaincluding papillary thyroid carcinoma; choriocarcinoma; Ewing's sarcoma;osteosarcoma; rhabdomyosarcoma; Kaposi's sarcoma; lymphoma includingBurkitt's lymphoma, Hodgkin's lymphoma, MALT lymphoma; multiplemyelomas; and virally induced tumors (especially such cancer is selectedfrom melanoma; lung cancer; bladder cancer; renal carcinomas;gastro-intestinal cancers; endometrial cancer; ovarian cancer; cervicalcancer; and neuroblastoma);wherein said compound is optionally used in combination with one or morechemotherapy agents and/or radiotherapy and/or targeted therapy;wherein in compounds of the formula (I)ring (A) in the fragment:

represents an aromatic 5- or 6-membered ring or a non-aromatic 5- or6-membered ring, which ring (A) is fused to the phenyl group, whereinindependently said ring (A) optionally contains one or two heteroatomsindependently selected from nitrogen, oxygen, and sulfur (notably suchfused group is benzofuranyl, benzothiophenyl, benzothiazolyl,benzoisothiazolyl, indolyl, indazolyl, naphthyl, quinolinyl,isoquinolinyl, 2,3-dihydro-benzo[b]thiophenyl, benzo[1,3]dioxolyl,1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, indanyl,5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,1,2,3,4-tetrahydro-quinolinyl);wherein said fragment is optionally substituted with (R¹)_(n); wherein(R¹)_(n) represents one, two, three, or four optional substituents (i.e.said fragment is unsubstituted, or substituted with one, two, three, orfour R¹), wherein said substituents R¹ are independently selected from(C₁₋₃)alkyl (especially methyl), (C₂₋₃)alkenyl (especially vinyl),(C₂₋₃)alkynyl (especially ethynyl), (C₁₋₃)alkoxy (especially methoxy,ethoxy, isopropoxy), halogen (especially fluoro, or chloro),—S—(C₁₋₃)alkyl (especially methylsulfanyl), (C₁₋₃)fluoroalkyl(especially trifluoromethyl), (C₁₋₃)fluoroalkoxy (especiallytrifluoromethoxy, difluoromethoxy), cyano, oxo, or amino;R³ represents hydrogen, methyl or trifluoromethyl (especially hydrogen);R^(4a) and R^(4b) independently represent hydrogen, methyl, or R^(4a)and R^(4b) together with the carbon atom to which they are attachedrepresent a cycloprop-1,1-diyl group;R^(5a) and R^(5b) independently represent hydrogen, methyl, or R^(5a)and R^(5b) together with the carbon atom to which they are attachedrepresent a cycloprop-1,1-diyl group;Ar¹ represents

-   (i) phenyl, or 5- or 6-membered heteroaryl (notably 5-membered    heteroaryl, especially thiophenyl or thiazolyl); wherein said phenyl    or 5- or 6-membered heteroaryl independently is mono-, di- or    tri-substituted, wherein the substituents are independently selected    from    -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl, isopropyl,        n-butyl, isobutyl, 1-methyl-propan-1-yl, tert.-butyl,        3-methyl-butyl);    -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy, isopropoxy,        n-butoxy, isobutoxy);    -   (C₁₋₃)fluoroalkyl, wherein said (C₁₋₃)fluoroalkyl is optionally        substituted with hydroxy (especially trifluoromethyl,        2,2,2-trifluoro-1-hydroxy-ethyl);    -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,        trifluoromethoxy, 2,2,2-trifluoroethoxy);    -   halogen (especially fluoro, chloro, bromo);    -   cyano;    -   (C₃₋₆)cycloalkyl, wherein said (C₃₋₆)cycloalkyl is unsubstituted        or mono-substituted with amino (especially cyclopropyl,        1-amino-cyclopropyl);    -   (C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein said        (C₄₋₆)cycloalkyl containing a ring oxygen atom is unsubstituted        or mono-substituted with hydroxy (especially        3-hydroxy-oxetan-3-yl);    -   (C₃₋₆)cycloalkyl-oxy (especially cyclobutyl-oxy,        cyclopentyl-oxy);    -   hydroxy;    -   —X¹—CO—R^(O1), wherein        -   X¹ represents a direct bond, (C₁₋₃)alkylene (especially            —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—), —O—(C₁₋₃)alkylene-*            (especially —O—CH₂—*, —O—CH(CH₃)—*, —O—C(CH₃)₂—*,            —O—CH₂—CH₂—*), —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂—*,            —NH—CH(CH₃)—*), —S—CH₂—*, —CF₂—, —CH═CH—, —CH═CH—, —NH—CO—*,            —CO—, or (C₃₋₅)cycloalkylene; wherein the asterisks indicate            the bond that is linked to the —CO—R^(O1) group; and        -   R^(O1) represents            -   —OH;            -   —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);            -   —NH—SO₂—R^(S3) wherein R^(S3) represents (C₁₋₄)alkyl,                (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl optionally                contains a ring oxygen atom,                (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                (C₃₋₆)cycloalkyl optionally contains a ring oxygen atom,                (C₁₋₃)fluoroalkyl, or —NH₂;            -   —O—CH₂—CO—R^(O4), wherein R^(O4) represents hydroxy, or                (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂;            -   —O—CH₂—O—CO—R^(O5), wherein R^(O5) represents                (C₁₋₄)alkyl or (C₁₋₄)alkoxy;            -   —O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ (especially                —O—CH₂—CH₂—N(CH₃)₂); or            -   (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;        -   [wherein in particular such group —X¹—CO—R^(O1) represents            —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH, —O—CH(CH₃)—COOH,            —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH, —NH—CH₂—COOH,            —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH, —CO—NH—SO₂—CH₃,            —CO—NH—SO₂—C(CH₃)₂, —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅,            —CO—NH—SO₂—NH₂, —CO—O—CH₂—COOH, —CO—O—CH₂—CH₂—N(CH₃)₂,            —CO—O—CH₂—CO—N(CH₃)₂, —CO—O—CH₂—O—CO—O—C₂H₅,            —CO—O—CH₂—O—CO-propyl,            (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—, —CH₂—COOH,            —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—COOH, —CH═CH—COOH,            —CH═CH—CO—O—C₂H₅, —CF₂—COOH, —NH—CO—COOH, —CO—COOH,            1-carboxy-cyclopropan-1-yl];    -   —CO—CH₂—OH;

-   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;    -   hydroxy-(C₁₋₄)alkyl (especially hydroxymethyl, 1-hydroxy-ethyl);    -   dihydroxy-(C₂₋₄)alkyl (especially 1,2-dihydroxyethyl);    -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);    -   (C₁₋₄)alkoxy-(C₂₋₄)alkoxy (especially 2-methoxy-ethoxy);    -   —(CH₂)_(r)—CO—NR^(N3)R^(N4) wherein r represents the integer 0        or 1; and wherein R^(N3) and R^(N4) independently represent        hydrogen, (C₁₋₄)alkyl, hydroxy-(C₂₋₄)alkyl,        (C₁₋₃)alkoxy-(C₂₋₄)alkyl, or hydroxy (wherein preferably at        least one of R^(N3) and R^(N4) represents hydrogen; and wherein        particular examples of such group —CO—NR^(N3)R^(N4) are —CO—NH₂,        —CO—NH(CH₃), —CO—NH(C₂H₅), —CH₂—CO—NH₂, —CO—NH—C₂H₄—OH,        —CO—NH—C₂H₄—OCH₃, or —CO—N(CH₃)₂, —CO—NH-isopropyl, or        —CO—NH—OH);    -   —X²—NR^(N1)R^(N2), wherein X² represents —(CH₂)_(m)—, wherein m        represents the integer 0 or 1; or X² represents        —O—CH₂—CH₂—*,wherein the asterisk indicates the bond that is        linked to the —NR^(N1)R^(N2) group; and wherein        -   R^(N1) and R^(N2) independently represent hydrogen,            (C₁₋₄)alkyl, (C₁₋₄)alkoxy-(C₂₋₄)alkyl, (C₃₋₆)cycloalkyl, or            (C₂₋₃)fluoroalkyl;        -   or R^(N1) independently represents hydrogen or (C₁₋₄)alkyl,            and R^(N2) independently represents —CO—H, —CO—(C₁₋₃)alkyl,            —CO—(C₁₋₃)alkylene-OH, or —CO—O—(C₁₋₃)alkyl;        -   or R^(N1) and R^(N2) together with the nitrogen to which            they are attached form a 4-, 5- or 6-membered saturated ring            optionally containing one ring oxygen or ring sulfur atom,            wherein said ring is unsubstituted, or mono-substituted with            oxo on a ring carbon atom, or disubstituted with oxo on a            ring sulfur atom;        -   (especially such group —X²—NR^(N1)R^(N2) represents amino,            methylamino, ethylamino, propylamino, amino-methyl,            methylamino-methyl, isobutylamino-methyl,            cyclopropylamino-methyl, cyclobutylamino-methyl,            (2-methoxyethyl)amino-methyl, (2,2,2-trifluoro-ethyl)-amino;            or —NH—CO—H, —N(C₂H₅)—CO—H, —NH—CO—C₂H₅, —NH—CO—CH₂—CH₂—OH,            —NH—CO—O—CH₃, —N(CH₃)—CO—O—CH₃; or pyrrolidin-1-yl,            2-oxo-pyrrolidin-1-yl, 1,1-dioxo-isothiazolidin-2-yl,            morpholin-4-yl, azetidin-1-yl, or piperidin-1-yl; or            2-(dimethylamino)-ethoxy);    -   —NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6) independently        represent hydrogen or (C₁₋₄)alkyl (wherein preferably at least        one of R^(N5) and R^(N6) represents hydrogen; and wherein        particular examples of such group —NH—CO—NR^(N)R^(N6) are        —NH—CO—NH₂, —NH—CO—NH—C₂H₅);    -   —SO₂—R^(S1) wherein R^(S1) represents hydroxy, (C₁₋₄)alkyl        (especially methyl), or —NR^(N7)R^(N8) wherein R^(N7) and R^(N8)        independently represent hydrogen or (C₁₋₃)alkyl (wherein        preferably at least one of R^(N7) and R^(N8) represents        hydrogen; and wherein particular examples of such group        —SO₂—R^(S1) are —SO₂—CH₃, —SO₂—NH₂, —SO₂—OH, —SO₂—NH—CH₃);    -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl (especially        methyl, ethyl, n-propyl, isopropyl, isobutyl), (C₃₋₆)cycloalkyl        optionally containing one ring oxygen atom (especially        cyclobutyl, oxetan-3-yl);    -   —(CH₂)_(q)-HET¹, wherein q represents the integer 0, 1 or 2        (especially q is 0, i.e. HET¹ is linked to Ar by a direct bond);        and wherein HET¹ represents        5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its        tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl),        3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its        tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl), or        5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its        tautomeric form 5-mercapto-[1,2,4]oxadiazol-3-yl);    -   —(CH₂)_(p)-HET, wherein p represents the integer 0 or 1        (especially p is 0, i.e. HET is linked to Ar¹ by a direct bond);        and wherein HET represents a 5- or 6-membered heteroaryl        (especially 5-membered heteroaryl selected from oxazolyl,        isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,        imidazolyl, pyrazolyl, triazolyl, and tetrazolyl), wherein said        5- or 6-membered heteroaryl is unsubstituted, or mono- or        di-substituted, wherein the substituents are independently        selected from (C₁₋₄)alkyl (especially methyl), (C₁₋₄)alkoxy        (especially methoxy), —COOH, hydroxy, hydroxy-(C₁₋₃)alkyl        (especially hydroxymethyl), (C₃₋₅)cycloalkyl optionally        containing one ring oxygen atom (especially cyclopropyl,        oxetan-3-yl), or —NR^(N9)R^(N10) wherein R^(N9) and R^(N10)        independently represent hydrogen, (C₁₋₃)alkyl (especially        methyl), or hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);        (especially such group —(CH₂)_(p)-HET is 1H-tetrazol-5-yl,        3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl,        3-amino-isoxazol-5-yl, 2-amino-oxazol-5-yl,        5-amino-[1,3,4]thiadiazol-2-yl,        5-methylamino-[1,3,4]thiadiazol-2-yl,        5-methoxy-[1,2,4]oxadiazol-3-yl, 5-amino-[1,2,4]oxadiazol-3-yl,        5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,        5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,        5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,        5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl)

-   (ii) or Ar¹ represents 8- to 10-membered bicyclic heteroaryl    (notably 9- or 10-membered bicyclic heteroaryl; especially    indazolyl, benzoimidazolyl, indolyl, benzotriazolyl, benzofuranyl,    benzooxazolyl, quinoxalinyl, isoquinolinyl, quinolinyl,    pyrrolopyridinyl, or imidazopyridinyl); wherein said 8- to    10-membered bicyclic heteroaryl independently is unsubstituted,    mono-, or di-substituted, wherein the substituents are independently    selected from (C₁₋₄)alkyl (especially methyl); (C₁₋₄)alkoxy    (especially methoxy); (C₁₋₃)fluoroalkyl (especially    trifluoromethyl); (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy);    halogen; cyano; hydroxy, or —(C₀₋₃)alkylene-COOR^(O2) wherein R^(O2)    represents hydrogen or (C₁₋₄)alkyl (especially such group    —(C₀₋₃)alkylene-COOR^(O2) is —COOH); (especially such 8- to    10-membered bicyclic heteroaryl, if unsubstituted, is    1H-benzoimidazol-5-yl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-indol-2-yl,    1H-indazol-5-yl, isoquinolin-7-yl, quinolin-6-yl; or, if    substituted, is 3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl,    5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl,    7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl,    6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl,    3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or    2-carboxy-benzofuran-6-yl);

-   (iii) or Ar¹ represents a group of the structure (Ar-III):

-   -   wherein ring (B) represents a non-aromatic 5- or 6-membered ring        fused to the phenyl group, wherein ring (B) comprises one or two        heteroatoms independently selected from nitrogen and oxygen        (notably such group (Ar-III) is 2,3-dihydro-benzofuranyl,        2,3-dihydro-1H-indolyl, 2,3-dihydro-benzo[1,4]dioxinyl,        2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl,        2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydro-isoindolyl,        2,3-dihydro-benzooxazolyl, 1,2,3,4-tetrahydro-quinazolinyl,        1,2,3,4-tetrahydro-isoquinolinyl, or        1,2,3,4-tetrahydro-phthalazinyl); wherein said ring (B)        independently is unsubstituted, mono-, or di-substituted,        wherein the substituents are independently selected from oxo,        (C₁₋₆)alkyl (especially methyl, ethyl, propyl, butyl, isobutyl)        and —(C₀₋₃)alkylene-COOR^(O3) wherein R^(O3) represents hydrogen        or (C₁₋₃)alkyl (especially such group (Ar-III) is        2-oxo-2,3-dihydro-benzooxazol-6-yl,        3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,        1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,        2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, or        1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl).

In a sub-embodiment, Ar¹ especially represents

-   -   phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or        5- or 6-membered heteroaryl independently is mono-, di- or        tri-substituted (especially di-substituted),        -   wherein one of said substituents is selected from            (C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein said            (C₄₋₆)cycloalkyl containing a ring oxygen atom is            unsubstituted or mono-substituted with hydroxy; hydroxy;

-   -   X¹—CO—R^(O1); 2-hydroxy-3,4-dioxo-cyclobut-1-enyl;        hydroxy-(C₂₋₄)alkoxy; —(CH₂)_(r)—CO—NR^(N3)R^(N4);        —NH—CO—NR^(N5)R^(N6); —SO₂—R^(S1); —(CH₂)_(q)-HET¹;        —(CH₂)_(p)-HET;        -   and the other of said substituents, if present,            independently are selected from (C₁₋₆)alkyl; (C₁₋₄)alkoxy;            (C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy; halogen; cyano;            (C₃₋₆)cycloalkyl, wherein said (C₃₋₆)cycloalkyl is            unsubstituted or mono-substituted with amino;            (C₃₋₆)cycloalkyl-oxy; hydroxy; hydroxy-(C₁₋₄)alkyl;            dihydroxy-(C₂₋₄)alkyl; hydroxy-(C₂₋₄)alkoxy;            (C₁₋₄)alkoxy-(C₂₋₄)alkoxy; —X²—NR^(N1)R^(N2); —S—R^(S2);    -   wherein the above groups and substituents are as defined in        embodiment 1).    -   or Ar¹ represents 8- to 10-membered bicyclic heteroaryl as        defined in embodiment 1); wherein said 8- to 10-membered        bicyclic heteroaryl independently is unsubstituted, mono-, or        di-substituted, wherein the substituents are independently        selected from (C₁₋₄)alkyl; (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl;        (C₁₋₃)fluoroalkoxy; halogen; cyano; hydroxy, or        —(C₀₋₃)alkylene-COOR^(O2) wherein R^(O2) represents hydrogen or        (C₁₋₄)alkyl;    -   or Ar¹ represents a group of the structure (Ar-III) as defined        in embodiment 1).

The compounds of formulae (I), (II), or (III) may contain one or morestereogenic or asymmetric centers, such as one or more asymmetric carbonatoms, which are allowed to be present in (R)- as well as(S)-configuration. The compounds of formulae (I), (II), or (III) mayfurther encompass compounds with one or more double bonds which areallowed to be present in Z- as well as E-configuration and/or compoundswith substituents at a ring system which are allowed to be present,relative to each other, in cis- as well as trans-configuration. Thecompounds of formulae (I), (II), or (III) may thus be present asmixtures of stereoisomers or preferably as pure stereoisomers. Mixturesof stereoisomers may be separated in a manner known to a person skilledin the art.

In case a particular compound (or generic structure) is designated as(R)- or (S)-enantiomer, such designation is to be understood asreferring to the respective compound (or generic structure) in enriched,especially essentially pure, enantiomeric form. Likewise, in case aspecific asymmetric center in a compound is designated as being in (R)-or (S)-configuration or as being in a certain relative configuration,such designation is to be understood as referring to the compound thatis in enriched, especially essentially pure, form with regard to therespective configuration of said asymmetric center. In analogy, cis- ortrans-designations are to be understood as referring to the respectivestereoisomer of the respective relative configuration in enriched,especially essentially pure, form. Likewise, in case a particularcompound (or generic structure) is designated as Z- or E-stereoisomer(or in case a specific double bond in a compound is designated as beingin Z- or E-configuration), such designation is to be understood asreferring to the respective compound (or generic structure) in enriched,especially essentially pure, stereoisomeric form (or to the compoundthat is in enriched, especially essentially pure, form with regard tothe respective configuration of the double bond).

The term “enriched”, when used in the context of stereoisomers, is to beunderstood in the context of the present invention to mean that therespective stereoisomer is present in a ratio of at least 70:30,especially of at least 90:10 (i.e., in a purity of at least 70% byweight, especially of at least 90% by weight), with regard to therespective other stereoisomer/the entirety of the respective otherstereoisomers.

The term “essentially pure”, when used in the context of stereoisomers,is to be understood in the context of the present invention to mean thatthe respective stereoisomer is present in a purity of at least 95% byweight, especially of at least 99% by weight, with regard to therespective other stereoisomer/the entirety of the respective otherstereoisomers.

The present invention also includes isotopically labelled, especially ²H(deuterium) labelled compounds of formulae (I), (II), or (III) accordingto embodiments 1) to 29), which compounds are identical to the compoundsof formulae (I), (II), or (Ill) except that one or more atoms have eachbeen replaced by an atom having the same atomic number but an atomicmass different from the atomic mass usually found in nature.Isotopically labelled, especially ²H (deuterium) labelled compounds offormulae (I), (II), or (III) and salts thereof are within the scope ofthe present invention. Substitution of hydrogen with the heavier isotope²H (deuterium) may lead to greater metabolic stability, resulting e.g.in increased in-vivo half-life or reduced dosage requirements, or maylead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. inan improved safety profile. In one embodiment of the invention, thecompounds of formulae (I), (II), or (III) are not isotopically labelled,or they are labelled only with one or more deuterium atoms. In asub-embodiment, the compounds of formulae (I), (II), or (III) are notisotopically labelled at all. Isotopically labelled compounds offormulae (I), (II), or (III) may be prepared in analogy to the methodsdescribed hereinafter, but using the appropriate isotopic variation ofsuitable reagents or starting materials.

In this patent application, a bond drawn as a dotted line shows thepoint of attachment of the radical drawn. For example, the radical drawnbelow

is the 2-methyl-1H-indol-1-yl group.

In some instances, the compounds of formulae (I), (II), or (III) maycontain tautomeric forms. Such tautomeric forms are encompassed in thescope of the present invention. In case tautomeric forms exist of acertain residue, and only one form of such residue is disclosed ordefined, the other tautomeric form(s) are understood to be encompassedin such disclosed residue. For example the group2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl is to be understood as alsoencompassing its tautomeric forms 2-hydroxy-1H-benzo[d]imidazol-5-yl and2-hydroxy-3H-benzo[d]imidazol-5-yl. Similarly,5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (alternatively named5-oxo-4H-[1,2,4]oxadiazol-3-yl) encompasses its tautomeric form5-hydroxy-[1,2,4]oxadiazol-3-yl, and3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (alternatively named3-oxo-2H-[1,2,4]oxadiazol-5-yl) encompasses its tautomeric form3-hydroxy-[1,2,4]oxadiazol-5-yl.

Where the plural form is used for compounds, salts, pharmaceuticalcompositions, diseases and the like, this is intended to mean also asingle compound, salt, or the like.

Any reference to compounds of formulae (I), (II), or (III) according toembodiments 1) to 29) is to be understood as referring also to the salts(and especially the pharmaceutically acceptable salts) of suchcompounds, as appropriate and expedient.

The term “pharmaceutically acceptable salts” refers to salts that retainthe desired biological activity of the subject compound and exhibitminimal undesired toxicological effects. Such salts include inorganic ororganic acid and/or base addition salts depending on the presence ofbasic and/or acidic groups in the subject compound. For reference seefor example “Handbook of Pharmaceutical Salts. Properties, Selection andUse.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008;and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quéré(Eds.), RSC Publishing, 2012.

Definitions provided herein are intended to apply uniformly to thecompounds of formulae (I), (II), or (III), as defined in any one ofembodiments 1) to 22), and, mutatis mutandis, throughout the descriptionand the claims unless an otherwise expressly set out definition providesa broader or narrower definition. It is well understood that adefinition or preferred definition of a term defines and may replace therespective term independently of (and in combination with) anydefinition or preferred definition of any or all other terms as definedherein. Whenever the group Ar¹ or substituents thereof are furtherdefined, such definitions are intended to apply mutatis mutandis also tothe groups (Ar-I), (Ar-II), and (Ar-III) and their respectivesubstituents.

Whenever a substituent is denoted as optional, it is understood thatsuch substituent may be absent (i.e. the respective residue isunsubstituted with regard to such optional substituent), in which caseall positions having a free valency (to which such optional substituentcould have been attached to; such as for example in an aromatic ring thering carbon atoms and/or the ring nitrogen atoms having a free valency)are substituted with hydrogen where appropriate. Likewise, in case theterm “optionally” is used in the context of (ring) heteroatom(s), theterm means that either the respective optional heteroatom(s), or thelike, are absent (i.e. a certain moiety does not contain heteroatom(s)/Iis a carbocycle/or the like), or the respective optional heteroatom(s),or the like, are present as explicitly defined.

The term “halogen” means fluorine, chlorine, bromine, or iodine;especially fluorine, chlorine, or bromine; preferably fluorine orchlorine.

The term “alkyl”, used alone or in combination, refers to a saturatedstraight or branched chain hydrocarbon group containing one to sixcarbon atoms. The term “(C_(x-y))alkyl” (x and y each being an integer),refers to an alkyl group as defined before, containing x to y carbonatoms. For example a (C₁₋₆)alkyl group contains from one to six carbonatoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert.-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl and3,3-dimethyl-butyl. For avoidance of any doubt, in case a group isreferred to as e.g. propyl or butyl, it is meant to be n-propyl,respectively n-butyl. Preferred are methyl and ethyl. Most preferred ismethyl. Preferred for substituents of Ar¹ being phenyl or 5- or6-membered heteroaryl are methyl, ethyl, propyl, isobutyl,1-methyl-propan-1-yl, tert.-butyl, 3-methyl-butyl.

The term “—(C_(x-y))alkylene-”, used alone or in combination, refers tobivalently bound alkyl group as defined before containing x to y carbonatoms. Preferably, the points of attachment of a —(C_(1-y))alkylenegroup are in 1,1-diyl, in 1,2-diyl, or in 1,3-diyl arrangement. In casea (C_(0-y))alkylene group is used in combination with anothersubstituent, the term means that either said substituent is linkedthrough a (C_(1-y))alkylene group to the rest of the molecule, or it isdirectly attached to the rest of the molecule (i.e. a (C₀)alkylene grouprepresents a direct bond linking said substituent to the rest of themolecule). The alkylene group —C₂H₄— refers to —CH₂—CH₂— if notexplicitly indicated otherwise. For the linker X¹, examples of(C₁₋₃)alkylene groups are —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, and —CH₂—CH₂—,especially —CH₂— and —CH₂—CH₂—. Examples of (C₀₋₃)alkylene groups asused in the substituents —(C₀₋₃)alkylene-COOR^(O2) and(C₀₋₃)alkylene-COOR^(O3), respectively, are (C₀)alkylene, and methylene,respectively.

The term “alkoxy”, used alone or in combination, refers to an alkyl-O—group wherein the alkyl group is as defined before. The term“(C_(x-y))alkoxy” (x and y each being an integer) refers to an alkoxygroup as defined before containing x to y carbon atoms. For example a(C₁₋₄)alkoxy group means a group of the formula (C₁₋₄)alkyl-O— in whichthe term “(C₁₋₄)alkyl” has the previously given significance. Examplesof alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are ethoxy andespecially methoxy. Preferred for substituents of Ar¹ being phenyl or 5-or 6-membered heteroaryl are methoxy, ethoxy, propoxy, butoxy,isobutoxy.

The term “fluoroalkyl”, used alone or in combination, refers to an alkylgroup as defined before containing one to three carbon atoms in whichone or more (and possibly all) hydrogen atoms have been replaced withfluorine. The term “(C_(x-y))fluoroalkyl” (x and y each being aninteger) refers to a fluoroalkyl group as defined before containing x toy carbon atoms. For example a (C₁₋₃)fluoroalkyl group contains from oneto three carbon atoms in which one to seven hydrogen atoms have beenreplaced with fluorine. Representative examples of fluoroalkyl groupsinclude trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and2,2,2-trifluoroethyl. Preferred are (C₁)fluoroalkyl groups such astrifluoromethyl. An example of “(C₁₋₃)fluoroalkyl, wherein said(C₁₋₃)fluoroalkyl is optionally substituted with hydroxy” is2,2,2-trifluoro-1-hydroxy-ethyl.

The term “fluoroalkoxy”, used alone or in combination, refers to analkoxy group as defined before containing one to three carbon atoms inwhich one or more (and possibly all) hydrogen atoms have been replacedwith fluorine. The term “(C_(x-y))fluoroalkoxy” (x and y each being aninteger) refers to a fluoroalkoxy group as defined before containing xto y carbon atoms. For example a (C₁₋₃)fluoroalkoxy group contains fromone to three carbon atoms in which one to seven hydrogen atoms have beenreplaced with fluorine. Representative examples of fluoroalkoxy groupsinclude trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy,2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are(C₁)fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy, aswell as 2,2,2-trifluoroethoxy.

The term “cycloalkyl”, used alone or in combination, refers to asaturated monocyclic hydrocarbon ring containing three to six carbonatoms. The term “(C_(x-y))cycloalkyl” (x and y each being an integer),refers to a cycloalkyl group as defined before containing x to y carbonatoms. For example a (C₃₋₆)cycloalkyl group contains from three to sixcarbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl. Preferred are cyclopropyl,cyclobutyl, and cyclopentyl; especially cyclopropyl. An example ofcycloalkyl groups containing one ring oxygen atom is especiallyoxetanyl. Examples of (C₃₋₆)cycloalkyl groups wherein said(C₃₋₆)cycloalkyl is optionally mono-substituted with amino arecyclopropyl, 1-amino-cyclopropyl. Examples of (C₃₋₆)cycloalkyl groupswherein said (C₃₋₆)cycloalkyl is mono-substituted with —COOH are1-carboxy-cyclopropyl, 1-carboxy-cyclopentyl.

The term “—(C_(x-y))cycloalkylene-”, used alone or in combination,refers to bivalently bound cycloalkyl group as defined before containingx to y carbon atoms. Preferably, the points of attachment of anybivalently bound cycloalkyl group are in 1,1-diyl, or in 1,2-diylarrangement. Examples are cyclopropan-1,1-diyl, cyclopropan-1,2-diyl,and cyclopentan-1,1-diyl; preferred is cyclopropan-1,1-diyl.

Examples of (C₃₋₆)cycloalkyl-oxy are cyclobutyl-oxy, andcyclopentyl-oxy.

Alkylated amino groups —N[(C₁₋₄)alkyl]₂ as used in groups —X¹—CO—R¹,wherein R^(O1) represents —O—CH₂—CO—R⁴, wherein R^(O4) represents—N[(C₁₋₄)alkyl]₂; or wherein R^(O1) represents—O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ are such that the two respective (C₁₋₄)alkylgroups are independently selected. A preferred example of such aminogroup —N[(C₁₋₄)alkyl]₂ is —N(CH₃)₂.

The term “heterocycle”, used alone or in combination, and if notexplicitly defined in a broader or more narrow way, refers to asaturated monocyclic hydrocarbon ring containing one or two (especiallyone) ring heteroatoms independently selected from nitrogen, sulfur, andoxygen (especially one nitrogen atom, two nitrogen atoms, one nitrogenatom and one oxygen atom, or one nitrogen atom and one sulfur atom). Theterm “(C_(x-y))heterocycle” refers to such a heterocycle containing x toy ring atoms. Heterocycles are unsubstituted or substituted asexplicitly defined.

A group composed of a “non-aromatic 5- or 6-membered ring fused to thephenyl group, wherein ring (B) comprises one or two heteroatomsindependently selected from nitrogen and oxygen” as used for (Ar-III)refers to phenyl groups which are fused to a (Cs₅₋₆)heterocycle asdefined before. Examples are 2,3-dihydro-benzofuranyl,2,3-dihydro-1H-indolyl, 2,3-dihydro-benzo[1,4]dioxinyl,2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl,2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydro-isoindolyl,3-dihydro-benzooxazol-6-yl, 2,3-dihydro-benzooxazol-5-yl,1,2,3,4-tetrahydro-quinazolin-6-yl, 1,2,3,4-tetrahydro-quinazolin-7-yl,1,2,3,4-tetrahydro-isoquinolin-6-yl, and1,2,3,4-tetrahydro-phthalazin-6-yl. The above groups are unsubstituted,mono-, or di-substituted, wherein the substituents are independentlyselected from oxo, (C₁₋₆)alkyl, and —(C₀₋₃)alkylene-COOR^(O3) whereinR^(O3) represents hydrogen or (C₁₋₃)alkyl (especially methyl);especially substituents are independently selected from oxo, methyl,ethyl, propyl, butyl, isobutyl, or —COOH; wherein the substituents areattached to the fused 5- or 6-membered non-aromatic ring. Oxosubstituents are preferably attached to a ring carbon atom which is inalpha position to a ring nitrogen atom. Preferred examples of suchgroups are 2,3-dihydro-benzofuranyl, 2,3-dihydro-1H-indolyl,2,3-dihydro-benzo[1,4]dioxinyl; as well as the oxosubstitutedheterocyclyl groups 3-oxo-2,3-dihydro-1H-indazolyl,2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl,3-oxo-2,3-dihydrobenzo[d]isoxazolyl, 2-oxo-1,3-dihydro-indolyl,1-oxo-2,3-dihydro-isoindolyl, 2-oxo-2,3-dihydro-benzooxazolyl,2-oxo-1,2,3,4-tetrahydro-quinazolinyl,1-oxo-1,2,3,4-tetrahydro-isoquinolinyl,1,4-dioxo-1,2,3,4-tetrahydro-phthalazinyl; wherein the above groupsoptionally carry one (further) substituent independently selected from(C₁₋₆)alkyl, and —(C₀₋₃)alkylene-COOR^(O3) wherein R^(O3) representshydrogen or (C₁₋₃)alkyl (especially methyl). Particular examples are2-oxo-2,3-dihydro-benzooxazol-6-yl,3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, or1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl.

For avoidance of doubt, certain groups having tautomeric forms which areconsidered predominantly non-aromatic, such as for example2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl groups, are defined herein as 8-to 10-membered partially aromatic fused bicyclic heterocyclyl groups,even though their corresponding tautomeric form(2-hydroxy-1H-benzo[d]imidazolyl) could also be considered as a 8- to10-membered bicyclic heteroaryl group.

Examples of the fragment:

wherein ring (A) represents an aromatic 5- or 6-membered ring which ring(A) is fused to the phenyl group, wherein said ring (A) optionallycontains one or two heteroatoms independently selected from nitrogen,oxygen, and sulfur are indolyl, isoindolyl, benzofuranyl,isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl,quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, andphthalazinyl (notably benzofuranyl, benzothiophenyl, benzothiazolyl,benzoisothiazolyl, indolyl, indazolyl, naphthyl, quinolinyl, andisoquinolinyl). The above groups are unsubstituted or substituted asexplicitly defined.

Examples of the fragment:

wherein ring (A) represents a non-aromatic 5- or 6-membered ring, whichring (A) is fused to the phenyl group, wherein said ring (A) optionallycontains one or two heteroatoms independently selected from nitrogen,oxygen, and sulfur are 2,3-dihydro-benzo[b]thiophenyl,benzo[1,3]dioxolyl, 1,3-dihydro-isobenzofuranyl,2,3-dihydro-benzofuranyl, indanyl, 5,6,7,8-tetrahydro-naphthalenyl,2,3-dihydro-benzo[1,4]dioxinyl, chromanyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, and 1,2,3,4-tetrahydro-quinolinyl.The above groups are unsubstituted or substituted as explicitly defined.

The term “aryl”, used alone or in combination, means phenyl or naphthyl,especially phenyl. The above-mentioned aryl groups are unsubstituted orsubstituted as explicitly defined.

Examples of the substituent Ar¹ representing phenyl are especially thosewhich are at least mono-substituted in para position with respect to thepoint of attachment of the rest of the molecule. In addition, such groupAr¹ representing phenyl may carry one or two further substituents,especially in one or both meta positions with respect to the point ofattachment of the rest of the molecule. The respective substituents ofsuch phenyl groups are as explicitly defined.

The term “heteroaryl”, used alone or in combination, means a 5- to10-membered monocyclic or bicyclic aromatic ring containing one to amaximum of four heteroatoms, each independently selected from oxygen,nitrogen and sulfur. Examples of such heteroaryl groups are 5-memberedheteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl,thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl; 6-membered heteroaryl groups such aspyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl; and 8- to 10-memberedbicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl,isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl,benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl,quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl,imidazopyridazinyl, and imidazothiazolyl. The above-mentioned heteroarylgroups are unsubstituted or substituted as explicitly defined.

For the substituent Ar¹ representing a “5- or 6-membered heteroaryl”,the term means the above-mentioned 5- or 6-membered groups such asespecially pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, isoxazolyl,thiazolyl or thiophenyl. Notably, the term refers to 5-membered groupssuch as especially thiazolyl or thiophenyl; in particular thiophen-2-yl,thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl. Preferred isthiophenyl, especially thiophen-2-yl; or thiazolyl, especiallythiazol-2-yl. The above groups are substituted as explicitly defined.Thiophen-2-yl or thiazol-2-yl are especially di-substituted with onesubstituent being in position 5, and a second substituent in position 4(and, for thiophen-2-yl, optionally a halogen substituent in position3).

For the substituent Ar¹ representing a “8- to 10-membered bicyclicheteroaryl” the term means the above-mentioned 8- to 10-memberedheteroaryl groups. Notably, the term refers to 9- or 10-memberedheteroaryl groups, such as especially indazolyl, benzoimidazolyl,indolyl, benzotriazolyl, benzooxazolyl, quinoxalinyl, isoquinolinyl,quinolinyl, pyrrolopyridinyl, and imidazopyridinyl. The above groups areunsubstituted or substituted as explicitly defined.

Particular examples are 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl,1H-indol-5-yl, 1H-indol-6-yl, 1-methyl-1H-indol-5-yl, 1H-indazol-5-yl,1H-indazol-6-yl, 1-methyl-1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl,3-methoxy-1H-indazol-6-yl, 6-methoxy-1H-indazol-5-yl,1H-benzoimidazol-5-yl, 2-methyl-1H-benzoimidazol-5-yl,2-trifluoromethyl-1H-benzoimidazol-5-yl, 1H-benzotriazol-5-yl,2-methyl-benzooxazol-5-yl, 2-methyl-benzooxazol-6-yl, quinoxalin-6-yl,isoquinolin-7-yl, quinolin-6-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl,1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl,1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl,2-carboxy-1H-indol-5-yl, 3-carboxy-1H-indol-6-yl,4-carboxy-1H-indol-2-yl, 5-carboxy-1H-indol-2-yl,6-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-2-yl,7-carboxy-1H-indol-4-yl, 7-carboxy-1-methyl-1H-indol-4-yl,5-(methoxycarbonyl)-1H-indol-2-yl, 6-(methoxycarbonyl)-1H-indol-2-yl),6-carboxy-benzofuran-2-yl, 3-carboxy-benzofuran-6-yl,2-carboxy-benzofuran-5-yl, and 2-carboxy-benzofuran-6-yl. Preferredexamples are 1H-benzoimidazol-5-yl, 1H-indol-6-yl, 1H-indol-5-yl,1H-indol-2-yl, 1H-indazol-5-yl, as well as 8- to 10-membered bicyclicheteroaryl which are mono-substituted with —(C₀₋₃)alkylene-COOR^(O2)such as 3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl,5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl,7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl,6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl,3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, and2-carboxy-benzofuran-6-yl.

For the substituent “—(CH₂)_(p)-HET, wherein p represents the integer 0or 1, and wherein HET represents a 5- or 6-membered heteroaryl”, such 5-or 6-membered heteroaryl is as defined before; notably a nitrogencontaining 5-membered heteroaryl such as especially tetrazolyl, oroxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, imidazolyl, pyrazolyl, or triazolyl. The above groups areunsubstituted or substituted as explicitly defined. The group—(CH₂)_(p)— is preferably absent, i.e. p represents the integer 0 andthe group HET is directly bound to Ar¹. Particular examples of—(CH₂)_(p)-HET are especially the —(CH₂)₀-HET groups 1H-tetrazol-5-yl,3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl; furtherexamples are 3-amino-isoxazol-5-yl, 2-amino-oxazol-5-yl,5-amino-[1,3,4]thiadiazol-2-yl, 5-methylamino-[1,3,4]thiadiazol-2-yl,5-methoxy-[1,2,4]oxadiazol-3-yl, 5-amino-[1,2,4]oxadiazol-3-yl,5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,5-methyl-1H-imidazol-4-yl, and 2,5-dimethyl-1H-imidazol-4-yl; as well as1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 3-methyl-pyrazol-1-yl,1-methyl-1H-pyrazol-3-yl, 5-methyl-1H-pyrazol-3-yl,3,5-dimethyl-pyrazol-1-yl, 4-carboxy-1H-pyrazol-3-yl, 1H-imidazol-2-yl,3-methyl-3H-imidazol-4-yl, 2-methyl-1H-imidazol-4-yl,1,5-dimethyl-1H-imidazol-2-yl, 1,2-dimethyl-1H-imidazol-4-yl,1,5-dimethyl-1H-imidazol-4-yl, 2-cyclopropyl-1H-imidazol-4-yl,2-cyclopropyl-1-methyl-1H-imidazol-4-yl, [1,2,4]oxadiazol-5-yl,5-methyl-[1,2,4]oxadiazol-3-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,5-methyl-[1,3,4]oxadiazol-2-yl, isothiazol-5-yl, thiazol-2-yl,thiazol-4-yl, 4-methyl-thiazol-2-yl, 2-methyl-thiazol-4-yl,2-amino-5-methyl-thiazol-4-yl, 4,5-dimethyl-thiazol-2-yl,4-carboxy-thiazol-2-yl, 2-carboxy-thiazol-4-yl, 2-hydroxy-thiazol-4-yl,2-amino-2-oxoethyl)thiazol-4-yl, isoxazol-3-yl, isoxazol-5-yl,3-methyl-isoxazol-5-yl, 4-methyl-isoxazol-5-yl,4-carboxy-3-methyl-isoxazol-5-yl, oxazol-5-yl, 2-methyl-oxazol-5-yl,2-(2-carboxyethyl)-oxazol-5-yl, 2-(2-carboxyethyl)-4-methyl-oxazol-5-yl,4H-[1,2,4]triazol-3-yl, 1H-[1,2,4]triazol-1-yl,2-methyl-2H-[1,2,4]triazol-3-yl, pyridin-2-yl, 4-fluoro-pyridin-2-yl,pyrimidin-2-yl, 5-fluoro-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl,4-methoxy-pyrimidin-2-yl, 6-methoxy-pyrimidin-4-yl,6-dimethylamino-pyrimidin-4-yl, pyrazin-2-yl, 6-methoxy-pyrazin-2-yl,6-methoxy-pyridazin-3-yl, 3H-imidazol-4-yl, 3H-[1,2,3]triazol-4-yl,oxazol-2-yl, and 4,5-dimethyl-oxazol-2-yl. For avoidance of doubt,certain groups having tautomeric forms which may be consideredpredominantly aromatic (such as for example 3-hydroxy-isoxazolyl or2-hydroxy-[1,3,4]oxadiazolyl groups) are defined herein as heteroarylgroups HET, even though their corresponding tautomeric form(3-oxo-2,3-dihydro-2H-isoxazolyl, respectively,2-oxo-2,3-dihydro-3H-[1,3,4]oxadiazolyl) could also be considered as anon-aromatic group. Likewise, certain groups having tautomeric formswhich may be considered predominantly non-aromatic (such as5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl or5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl) as defined for thesubstituent HET¹, are defined herein as not being part of substitutedheteroaryl groups as defined for HET, even though their correspondingtautomeric form (5-hydroxy-[1,2,4]oxadiazolyl, respectively,5-mercapto-[1,2,4]oxadiazolyl), could also be considered as anheteroaryl group.

It is understood that the corresponding tautomer is encompassed in therespective scope as defined.

The term “cyano” refers to a group —CN.

The term “amino” refers to a group —NH₂.

The term “oxo” refers to a group ═O which is preferably attached to achain or ring carbon or sulfur atom as for example in a carbonyl group—(CO)—, or a sulfonyl group —(SO₂)—.

Examples of “—X²—NR^(N1)R^(N2)” groups as used for substituents of Ar¹being phenyl or 5- or 6-membered heteroaryl are amino, methylamino,ethylamino, propylamino, amino-methyl, methylamino-methyl,isobutylamino-methyl, cyclopropylamino-methyl, cyclobutylamino-methyl,(2-methoxyethyl)amino-methyl, (2,2,2-trifluoro-ethyl)-amino; or—NH—CO—H, —N(C₂H₅)—CO—H, —NH—CO—C₂H₅, —NH—CO—CH₂—CH₂—OH, —NH—CO—O—CH₃,—N(CH₃)—CO—O—CH₃; or pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,1,1-dioxo-isothiazolidin-2-yl, morpholin-4-yl, azetidin-1-yl, orpiperidin-1-yl; and 2-(dimethylamino)-ethoxy.

Examples of a group “—NH—CO—NR^(N5)R^(N6)” as used for substituents ofthe group Ar¹ are ureido (—NH—CO—NH₂) and 3-ethylureido(—NH—CO—NH—C₂H₅).

Examples of a group “—(CH₂)_(r)—CO—NR^(N3)R^(N4) wherein r representsthe integer 0 or 1” as used for substituents of the group Ar¹ arepreferably groups wherein r represents the integer 0 and at least one ofR^(N3) and R^(N4) represents hydrogen (or less preferred, methyl).Particular examples of such group —CO—NR^(N3)R^(N4) are —CO—NH₂,—CO—NH(CH₃), —CO—N(CH₃)₂, —CO—NH(C₂H₅), —CO—NH—O-methyl, —CO—NH—O-ethyl,—CO—NH—O-isopropyl, —CO—NH—C₂H₄—OH, —CO—NH—O—C₂H₄—OH, —CO—NH—C₂H₄—OCH₃,—CO—NH—C₂H₄—N(CH₃)₂, and —CO—NH—O-benzyl. Further examples are—CO—NH-isopropyl and —CO—NH—OH, as well as —CO—N(CH₃)₂.

Examples of a group “—X¹—CO—R¹” as used for substituents of the groupAr¹ are especially the following groups:

-   -   a) X¹ represents a direct bond; and R^(O1) represents —OH; (i.e.        —X¹—CO—R^(O1) represents —COOH); or    -   b) X¹ represents a direct bond; and R^(O1) represents        —O—(C₁₋₄)alkyl (especially ethoxy, or methoxy); (i.e.        —X¹—CO—R^(O1) represents —CO—(C₁₋₄)alkoxy (especially        ethoxycarbonyl, methoxycarbonyl)); or    -   c) X¹ represents a direct bond; and R^(O1) represents        —NH—SO₂—R^(S3); wherein R^(S3) represents (C₁₋₄)alkyl;        (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl optionally        contains a ring oxygen atom; (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene        wherein the (C₃₋₆)cycloalkyl optionally contains a ring oxygen        atom; (C₁₋₃)fluoroalkyl; phenyl; or —NH₂; (i.e. —X¹—CO—R^(O1)        represents —CO—NH—SO₂—R^(S3) wherein R^(S3) represents the above        mentioned groups; notably methyl, ethyl, isopropyl, cyclopropyl,        trifluoromethyl, amino; especially —X¹—CO—R^(O1) represents        —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂, —CO—NH—SO₂-cyclopropyl,        —CO—NH—SO₂-ethyl, or —CO—NH—SO₂—NH₂); or    -   d) X¹ represents (C₁₋₃)alkylene (especially —CH₂—, —CH₂—CH₂—),        —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*, —O—CH(CH₃)—*,        —O—C(CH₃)₂—*, O—CH₂—CH₂—*), —NH—(C₁₋₃)alkylene-* (especially        —NH—CH₂—*, —NH—CH(CH₃)—*), —S—CH₂—*, —CF₂—, —CH═CH—, or —CH═CH—        [in a sub-embodiment X¹ represents especially —O—CH₂—*,        —NH—CH₂—*, —S—CH₂—*, or (C₁₋₃)alkylene]; wherein the asterisks        indicate the bond that is linked to the —CO—R^(O1) group; and        R^(O1) represents —OH (i.e. —X¹—CO—R^(O1) represents —X¹—COOH        wherein X¹ represents the above mentioned groups; especially        —X¹—CO—R^(O1) represents —O—CH₂—COOH or —NH—CH₂—COOH; as well as        —CH₂—COOH, —CH₂—CH₂—COOH, —CH═CH—COOH, —CH═CH—COOH,        —O—CH₂—CH₂—COOH, —O—CH(CH₃)—COOH, or —NH—CH(CH₃)—COOH); or    -   e) —X¹ represents —NH—CO—* or —CO—; wherein the asterisk        indicates the bond that is linked to the —CO—R^(O1) group; and        R^(O1) represents —OH (i.e. —X¹—CO—R^(O1) represents —X¹—COOH        wherein X¹ represents the above mentioned groups; especially        —X¹—CO—R^(O1) represents —NH—CO—COOH, —CO—COOH); or    -   f) X¹ represents (C₃₋₅)cycloalkylene; and R^(O1) represents —OH;        (i.e. —X¹—CO—R^(O1) represents (C₃₋₆)cycloalkyl which is        mono-substituted with COOH; especially —X¹—CO—R^(O1) represents        1-carboxy-cyclopropan-1-yl or 1-carboxy-cyclopentan-1-yl); or    -   g) X¹ represents a direct bond; and R^(O1) represents        —O—CH₂—CO—R^(O4), wherein R^(O4) represents hydroxy, or        (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂; especially —X¹—CO—R^(O1)        represents —CO—O—CH₂—COOH; or        wherein each of the groups a), b), c), d), e), f), and g) forms        a particular sub-embodiment.

Compounds of Formulae (I), (II), or (Ill) containing a group“—X¹—CO—R^(O1)” wherein X¹ represents —CH═CH— may be in E- orZ-configuration. Preferably, such groups are in E-configuration.

Whenever a group Ar¹ is substituted with a substituent comprising acarboxylic acid group —COOH (such as in the substituents—(C₀₋₃)alkylene-COOR² wherein R^(O2) represents hydrogen;—(C₀₋₃)alkylene-COOR^(O3) wherein R^(O3) represents hydrogen; or in thesubstituents —X¹—CO—R^(O1) wherein R^(O1) represents —OH, especially inthe —X¹—CO—R^(O1) groups a), d), e) and f) above) such carboxylic acidgroup may be present in form of a prodrug group. Such prodrugs areencompassed in the scope of the present invention. In certain instances,compounds comprising such carboxylic acid prodrug groups may as suchexhibit biological activity on the EP2 and/or EP4 receptor, whereas inother instances, such compounds comprising such carboxylic acid prodruggroups require (e.g. enzymatic) cleavage of the prodrug to exhibitbiological activity on the EP2 and/or EP4 receptor. Prodrugs of thecarboxylic acid functional group are well known in the art (see forexample J. Rautio (Ed.) Prodrugs and Targeted Delivery: Towards BetterADME Properties, Volume 47, Wiley 2010,ISBN: 978-3-527-32603-7; H. Maagin Stella, V., Borchardt, R., Hageman, M., Oliyai, R., Maag, H., Tilley,J. (Eds.) Prodrugs: Challenges and Rewards, Springer 2007, ISBN978-0-387-49785-3).

Particular examples of prodrugs, for example suitable for —X¹—COOHgroups are:

-   -   ester groups —X¹—CO—O—P¹ wherein P¹ is for example (C₁₋₄)alkyl;        (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl optionally        contains a ring oxygen atom; (C₃₋₆)cycloalkyl-(C₁₋₃)alkyl        wherein the (C₃₋₆)cycloalkyl optionally contains a ring oxygen        atom; (C₁₋₃)fluoroalkyl; hydroxy-(C₂₋₄)alkyl; or        (C₁₋₄)alkoxy-(C₂₋₄)alkyl (especially P1 is (C₁₋₄)alkyl, in        particular methyl or ethyl);    -   groups —X¹—CO—NH—SO₂—R^(S3) wherein R^(S3) represents        (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl        optionally contains a ring oxygen atom;        (C₃₋₆)cycloalkyl-(C₁₋₃)alkyl wherein the (C₃₋₆)cycloalkyl        optionally contains a ring oxygen atom; (C₁₋₃)fluoroalkyl, —NH₂;        (especially R^(S3) is (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl; in        particular methyl);    -   groups —X¹—CO—R^(O1) wherein R^(O1) represents —O—CH₂—CO—R^(O4),        wherein R^(O4) represents hydroxy, or (C₁₋₄)alkoxy, or        —N[(C₁₋₄)alkyl]₂ (especially —CO—O—CH₂—COOH,        —CO—O—CH₂—CO—N(CH₃)₂);    -   groups —X¹—CO—R^(O1) wherein R^(O1) represents        —O—CH₂—O—CO—R^(O5), wherein R^(O5) represents (C₁₋₄)alkyl or        (C₁₋₄)alkoxy (especially —CO—O—CH₂—O—CO—O-ethyl,        —CO—O—CH₂—O—CO-propyl);    -   groups —X¹—CO—R^(O1) wherein R^(O1) represents        —O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ (especially —CO—O—CH₂—CH₂—N(CH₃)₂);        and    -   groups —X¹—CO—R^(O1) wherein R^(O1) represents        5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-.

Examples of “hydroxy-(C₁₋₄)alkyl” groups as used for substituents of thegroup Ar¹ are hydroxymethyl and 1-hydroxy-ethyl.

An example of “dihydroxy-(C₂₋₄)alkyl” groups as used for substituents ofthe group Ar¹ is 1,2-dihydroxyethyl.

An example of “hydroxy-(C₂₋₄)alkoxy” groups as used for substituents ofthe group Ar¹ is 2-hydroxy-ethoxy.

An example of “(C₁₋₄)alkoxy-(C₂₋₄)alkoxy” groups as used forsubstituents of the group Ar¹ is 2-methoxy-ethoxy.

Examples of a group “—SO₂—R^(S1)” as used for substituents of the groupAr¹ are —SO₂—CH₃, —SO₂—NH₂, —SO₂—NH—CH₃.

Examples of a group “S—R^(S2)” as used for substituents of the group Ar¹are methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl,isobutylsulfanyl), cyclobutylsulfanyl, and (oxetan-3-yl)-sulfanyl.

An example of a “(C₁₋₄)alkoxy-(C₂₋₄)alkyl” group is 2-methoxyethyl.

An example of a “hydroxy-(C₂₋₄)alkoxy” group is 2-hydroxy-ethoxy.

An example of a “hydroxy-(C₂₋₄)alkyl” group is 2-hydroxy-ethyl.

An example of a “—CO—(C₁₋₄)alkoxy” group as used for substituents of thegroup Ar¹ is ethoxycarbonyl. Such groups may also be useful as prodrugsof the respective —COOH substituent.

Whenever the word “between” is used to describe a numerical range, it isto be understood that the end points of the indicated range areexplicitly included in the range. For example: if a temperature range isdescribed to be between 40° C. and 80° C., this means that the endpoints 40° C. and 80° C. are included in the range; or if a variable isdefined as being an integer between 1 and 4, this means that thevariable is the integer 1, 2, 3, or 4.

Unless used regarding temperatures, the term “about” placed before anumerical value “X” refers in the current application to an intervalextending from X minus 10% of X to X plus 10% of X, and preferably to aninterval extending from X minus 5% of X to X plus 5% of X. In theparticular case of temperatures, the term “about” placed before atemperature “Y” refers in the current application to an intervalextending from the temperature Y minus 10° C. to Y plus 10° C., andpreferably to an interval extending from Y minus 5° C. to Y plus 5° C.Besides, the term “room temperature” as used herein refers to atemperature of about 25° C.

Further embodiments of the invention are presented hereinafter:

2) Another embodiment relates to compounds as defined in to embodiment1), for use according to embodiment 1), wherein R^(4a) and R^(4b) bothrepresent hydrogen.3) Another embodiment relates to compounds as defined in toembodiments 1) or 2), for use according to embodiment 1), wherein R^(5a)and R^(5b) both represent hydrogen. Particular compounds of formula (I)are compounds wherein R^(4a) and R^(4b) both represent hydrogen; andR^(5a) and R^(5b) both represent hydrogen.4) Another embodiment relates to compounds of formula (I) as defined inembodiment 1), for use according to embodiment 1), which compounds arealso compounds of the formula (II)

whereinring (A) in the fragment:

represents an aromatic 5- or 6-membered ring or a non-aromatic 5- or6-membered ring, which ring (A) is fused to the phenyl group, whereinindependently said ring (A) optionally contains one or two heteroatomsindependently selected from nitrogen, oxygen, and sulfur (notably suchfused group is benzofuranyl, benzothiophenyl, benzothiazolyl,benzoisothiazolyl, indolyl, indazolyl, naphthyl, quinolinyl,isoquinolinyl, 2,3-dihydro-benzo[b]thiophenyl, benzo[1,3]dioxolyl,1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, indanyl,5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,1,2,3,4-tetrahydro-quinolinyl);wherein said fragment is optionally substituted with (R¹)_(n); wherein(R¹)_(n) represents one, two, three, or four optional substituents (i.e.said fragment is unsubstituted, or substituted with one, two, three, orfour R¹), wherein said substituents R¹ are independently selected from(C₁₋₃)alkyl (especially methyl), (C₂₋₃)alkenyl (especially vinyl),(C₂₋₃)alkynyl (especially ethynyl), (C₁₋₃)alkoxy (especially methoxy,ethoxy, isopropoxy), halogen (especially fluoro, or chloro),—S—(C₁₋₃)alkyl (especially methylsulfanyl), (C₁₋₃)fluoroalkyl(especially trifluoromethyl), (C₁₋₃)fluoroalkoxy (especiallytrifluoromethoxy, difluoromethoxy), cyano, oxo, or amino;R³ represents hydrogen, or methyl (especially hydrogen); andAr¹ represents

-   -   a phenyl group of the structure (Ar-I):

-   -   wherein        -   R^(p) represents            -   (C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein                said (C₄₋₆)cycloalkyl containing a ring oxygen atom is                unsubstituted or mono-substituted with hydroxy                (especially 3-hydroxy-oxetan-3-yl);            -   hydroxy;            -   —X¹—CO—R^(O1), wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂—*,                    —NH—CH(CH₃)—*), —S—CH₂—*, —CF₂—, —CH═CH—, —CH═CH—,                    —NH—CO—*, —CO—, or (C₃₋₅)cycloalkylene; wherein the                    asterisks indicate the bond that is linked to the                    —CO—R^(O1) group; and                -   R^(O1) represents                -   —OH;                -   —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -   —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;                -   —O—CH₂—CO—R^(O4), wherein R^(O4) represents hydroxy,                    or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂;                -   —O—CH₂—O—CO—R^(O5), wherein R^(O5) represents                    (C₁₋₄)alkyl or (C₁₋₄)alkoxy;                -   —O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ (especially                    —O—CH₂—CH₂—N(CH₃)₂); or                -   (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH,                —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CO—O—CH₂—COOH, —CO—O—CH₂—CH₂—N(CH₃)₂,                —CO—O—CH₂—CO—N(CH₃)₂, —CO—O—CH₂—O—CO—O—C₂H₅,                —CO—O—CH₂—O—CO-propyl,                (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—,                —CH₂—COOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—COOH,                —CH═CH—COOH, —CH═CH—CO—O—C₂H₅, —CF₂—COOH, —NH—CO—COOH,                —CO—COOH, 1-carboxy-cyclopropan-1-yl];

-   -   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;        -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);        -   —(CH₂)_(r)—CO—NR^(N3)R^(N4) wherein r represents the integer            0 or 1; and wherein R^(N3) and R^(N4) independently            represent hydrogen, (C₁₋₄)alkyl, hydroxy-(C₂₋₄)alkyl,            (C₁₋₃)alkoxy-(C₂₋₄)alkyl, or hydroxy (wherein preferably at            least one of R^(N3) and R^(N4) represents hydrogen; and            wherein particular examples of such group —CO—NR^(N3)R^(N4)            are —CO—NH₂, —CO—NH(CH₃), —CO—NH(C₂H₅), —CH₂—CO—NH₂,            —CO—NH—C₂H₄—OH, —CO—NH—C₂H₄—OCH₃, or —CO—N(CH₃)₂,            —CO—NH-isopropyl, or —CO—NH—OH);        -   —NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6) independently            represent hydrogen or (C₁₋₄)alkyl (wherein preferably at            least one of R^(N5) and R^(N6) represents hydrogen; and            wherein particular examples of such group            —NH—CO—NR^(N)R^(N6) are —NH—CO—NH₂, —NH—CO—NH—C₂H₅);        -   —(CH₂)_(q)-HET¹, wherein q represents the integer 0, 1 or 2            (especially q is 0, i.e. HET¹ is linked to Ar¹ by a direct            bond); and wherein HET¹ represents            5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl),            3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its            tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl), or            5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-mercapto-[1,2,4]oxadiazol-3-yl);        -   —(CH₂)_(p)-HET, wherein p represents the integer 0 or 1            (especially p is 0, i.e. HET is linked to Ar¹ by a direct            bond); and wherein HET represents a 5-membered heteroaryl            (especially oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,            isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,            triazolyl, or tetrazolyl), wherein said 5-membered            heteroaryl is unsubstituted, or mono- or di-substituted,            wherein the substituents are independently selected from            (C₁₋₄)alkyl (especially methyl), (C₁₋₄)alkoxy (especially            methoxy), —COOH, hydroxy, hydroxy-(C₁₋₃)alkyl (especially            hydroxymethyl), (C₃₋₅)cycloalkyl optionally containing one            ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or            —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently            represent hydrogen, (C₁₋₃)alkyl (especially methyl), or            hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);            (especially such group —(CH₂)_(p)-HET is 1H-tetrazol-5-yl,            3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl,            3-amino-isoxazol-5-yl, 2-amino-oxazol-5-yl,            5-amino-[1,3,4]thiadiazol-2-yl,            5-methylamino-[1,3,4]thiadiazol-2-yl,            5-methoxy-[1,2,4]oxadiazol-3-yl,            5-amino-[1,2,4]oxadiazol-3-yl,            5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,            5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,            5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,            5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl);

    -   R^(m1) represents        -   hydrogen;        -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl, isopropyl,            n-butyl, isobutyl);        -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,            isopropoxy, n-butoxy, isobutoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,            trifluoromethoxy, 2,2,2-trifluoroethoxy);        -   halogen (especially fluoro or chloro);        -   (C₃₋₆)cycloalkyl (especially cyclopropyl);        -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,            cyclobutyl-oxy, cyclopentyl-oxy);        -   hydroxy;        -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);        -   —X²—NR^(N1)R^(N2), wherein X² represents a direct bond; or            X² represents —O—CH₂—CH₂₋*, wherein the asterisk indicates            the bond that is linked to the —NR^(N1)R^(N2) group; and            wherein R^(N1) and R^(N2) independently represent hydrogen,            (C₁₋₄)alkyl (especially methyl), or (C₃₋₆)cycloalkyl            (especially cyclopropyl); (especially such group            —X²—NR^(N1)R^(N2) represents amino, methylamino, ethylamino,            propylamino; or 2-(dimethylamino)-ethoxy);        -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl (especially            methyl, ethyl, n-propyl, isopropyl, isobutyl),            (C₃₋₆)cycloalkyl optionally containing one ring oxygen atom            (especially cyclobutyl, oxetan-3-yl);        -   wherein in a sub-embodiment, R^(m1) especially is different            from hydrogen;

    -   R^(m2) represents hydrogen, methyl, fluoro, or chloro; and

    -   R^(o1) represents hydrogen; or, in case R^(m2) represents        hydrogen, R^(o1) represents hydrogen or fluoro;

    -   or Ar¹ represents a 5-membered heteroaryl group of the structure        (Ar-III):

-   -   wherein    -   Y represents CR⁸ wherein R⁸ represents especially hydrogen, or        halogen (notably fluoro, chloro); or Y represents N;    -   R⁷ represents        -   (C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein said            (C₄₋₆)cycloalkyl containing a ring oxygen atom is            unsubstituted or mono-substituted with hydroxy (especially            3-hydroxy-oxetan-3-yl);        -   —X¹—CO—R¹, wherein            -   X¹ represents a direct bond, (C₁₋₃)alkylene (especially                —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*, —O—CH(CH₃)—*,                —O—C(CH₃)₂—*, —O—CH₂—CH₂—*), —NH—(C₁₋₃)alkylene-*                (especially —NH—CH₂—*, —NH—CH(CH₃)—*), —S—CH₂—*, —CF₂—,                —CH═CH—, —CH≡CH—, —NH—CO—*, —CO—, or                (C₃₋₅)cycloalkylene; wherein the asterisks indicate the                bond that is linked to the —CO—R^(O1) group; and            -   R^(O1) represents                -   —OH;                -   —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -   —NH—SO₂—R³ wherein R^(S3) represents (C₁₋₄)alkyl,                    (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl                    optionally contains a ring oxygen atom,                    (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;                -   —O—CH₂—CO—R^(O4), wherein R^(O4) represents hydroxy,                    or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂;                -   —O—CH₂—O—CO—R^(O5), wherein R^(O5) represents                    (C₁₋₄)alkyl or (C₁₋₄)alkoxy;                -   —O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ (especially                    —O—CH₂—CH₂—N(CH₃)₂); or                -   (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;        -   [wherein in particular such group —X¹—CO—R^(O1) represents            —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH, —O—CH(CH₃)—COOH,            —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH, —NH—CH₂—COOH,            —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH, —CO—NH—SO₂—CH₃,            —CO—NH—SO₂—C(CH₃)₂, —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅,            —CO—NH—SO₂—NH₂, —CO—O—CH₂—COOH, —CO—O—CH₂—CH₂—N(CH₃)₂,            —CO—O—CH₂—CO—N(CH₃)₂, —CO—O—CH₂—O—CO—O—C₂H₅,            —CO—O—CH₂—O—CO-propyl,            (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—, —CH₂—COOH,            —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—COOH, —CH═CH—COOH,            —CH═CH—CO—O—C₂H₅, —CF₂—COOH, —NH—CO—COOH, —CO—COOH,            1-carboxy-cyclopropan-1-yl];

-   -   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;        -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);        -   —(CH₂)_(r)—CO—NR^(N3)R^(N4) wherein r represents the integer            0 or 1; and wherein R^(N3) and R^(N4) independently            represent hydrogen, (C₁₋₄)alkyl, hydroxy-(C₂₋₄)alkyl,            (C₁₋₃)alkoxy-(C₂₋₄)alkyl, or hydroxy (wherein preferably at            least one of R^(N3) and R^(N4) represents hydrogen; and            wherein particular examples of such group —CO—NR^(N3)R^(N4)            are —CO—NH₂, —CO—NH(CH₃), —CO—NH(C₂H₅), —CH₂—CO—NH₂,            —CO—NH—C₂H₄—OH, —CO—NH—C₂H₄—OCH₃, or —CO—N(CH₃)₂,            —CO—NH-isopropyl, or —CO—NH—OH);        -   —NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6) independently            represent hydrogen or (C₁₋₄)alkyl (wherein preferably at            least one of R^(N5) and R^(N6) represents hydrogen; and            wherein particular examples of such group            —NH—CO—NR^(N)R^(N6) are —NH—CO—NH₂, —NH—CO—NH—C₂H₅);        -   —(CH₂)_(q)-HET¹, wherein q represents the integer 0, 1 or 2            (especially q is 0, i.e. HET¹ is linked to Ar by a direct            bond); and wherein HET¹ represents            5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl),            3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its            tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl), or            5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-mercapto-[1,2,4]oxadiazol-3-yl);        -   —(CH₂)_(p)-HET, wherein p represents the integer 0 or 1            (especially p is 0, i.e. HET is linked to Ar¹ by a direct            bond); and wherein HET represents a 5-membered heteroaryl            (especially oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,            isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,            triazolyl, or tetrazolyl), wherein said 5-membered            heteroaryl is unsubstituted, or mono- or di-substituted,            wherein the substituents are independently selected from            (C₁₋₄)alkyl (especially methyl), (C₁₋₄)alkoxy (especially            methoxy), —COOH, hydroxy, hydroxy-(C₁₋₃)alkyl (especially            hydroxymethyl), (C₃₋₅)cycloalkyl optionally containing one            ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or            —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently            represent hydrogen, (C₁₋₃)alkyl (especially methyl), or            hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);            (especially such group —(CH₂)_(p)-HET is 1H-tetrazol-5-yl,            3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl,            3-amino-isoxazol-5-yl, 2-amino-oxazol-5-yl,            5-amino-[1,3,4]thiadiazol-2-yl,            5-methylamino-[1,3,4]thiadiazol-2-yl,            5-methoxy-[1,2,4]oxadiazol-3-yl,            5-amino-[1,2,4]oxadiazol-3-yl,            5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,            5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,            5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,            5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl);

    -   R⁶ represents        -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl, isopropyl,            n-butyl, isobutyl);        -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,            isopropoxy, n-butoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,            trifluoromethoxy, 2,2,2-trifluoroethoxy);        -   halogen (especially fluoro or chloro);        -   hydroxy;        -   (C₃₋₆)cycloalkyl (especially cyclopropyl);        -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,            cyclobutyl-oxy, cyclopentyl-oxy);        -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);        -   —X²—NR^(N1)R^(N2), wherein X² represents a direct bond; or            X² represents —O—CH₂—CH₂₋*, wherein the asterisk indicates            the bond that is linked to the —NR^(N1)R^(N2) group; and            wherein R^(N1) and R^(N2) independently represent hydrogen,            (C₁₋₄)alkyl, or (C₃₋₆)cycloalkyl; (especially such group            —X²—NR^(N1)R^(N2) represents amino, methylamino, ethylamino,            propylamino; or 2-(dimethylamino)-ethoxy);        -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl (especially            methyl, ethyl, n-propyl, isopropyl, isobutyl),            (C₃₋₆)cycloalkyl optionally containing one ring oxygen atom            (especially cyclobutyl, oxetan-3-yl);

    -   or Ar¹ represents 8- to 10-membered bicyclic heteroaryl (notably        9- or 10-membered bicyclic heteroaryl; especially indazolyl,        benzoimidazolyl, indolyl, benzofuranyl, benzooxazolyl,        quinoxalinyl, isoquinolinyl, or quinolinyl); wherein said 8- to        10-membered bicyclic heteroaryl independently is        mono-substituted with —(C₀₋₃)alkylene-COOR² wherein R^(O2)        represents hydrogen or (C₁₋₄)alkyl (especially methyl) (wherein        especially such group —(C₀₋₃)alkylene-COOR^(O2) is —COOH);        (especially such 8- to 10-membered bicyclic heteroaryl is        3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl,        5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl,        7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl,        6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl,        3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or        2-carboxy-benzofuran-6-yl);

    -   or Ar¹ represents a group of the structure (Ar-III):

-   -   which is selected from 2-oxo-2,3-dihydro-benzooxazol-6-yl,        3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,        1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,        2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, and        1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl.        5) Another embodiment relates to compounds as defined in        embodiment 4), for use according to embodiment 1), wherein Ar¹        represents    -   a phenyl group of the structure (Ar-I):

-   -   wherein        -   R^(p) represents            -   —X¹—CO—R¹, wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂—*,                    —NH—CH(CH₃)—*), —CH═CH—, —NH—CO—*, or                    (C₃₋₅)cycloalkylene; wherein the asterisks indicate                    the bond that is linked to the —CO—R^(O1) group; and                -   R^(O1) represents                -   —OH;                -   —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -   —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;                -   —O—CH₂—CO—R^(O4), wherein R^(O4) represents hydroxy,                    or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂;                -   —O—CH₂—O—CO—R⁵, wherein R^(O5) represents                    (C₁₋₄)alkyl or (C₁₋₄)alkoxy;                -   —O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ (especially                    —O—CH₂—CH₂—N(CH₃)₂); or                -   (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH,                —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CO—O—CH₂—COOH, —CO—O—CH₂—CH₂—N(CH₃)₂,                —CO—O—CH₂—CO—N(CH₃)₂, —CO—O—CH₂—O—CO—O—C₂H₅,                —CO—O—CH₂—O—CO-propyl,                (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—,                —CH₂—COOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—COOH,                —CH═CH—COOH, —NH—CO—COOH, 1-carboxy-cyclopropan-1-yl];

-   -   -   —CO—NR^(N3)R^(N4) wherein R^(N3) and R^(N4) independently            represent hydrogen, or (C₁₋₄)alkyl (wherein preferably at            least one of R^(N3) and R^(N4) represents hydrogen; and            wherein particular examples of such group —CO—NR^(N3)R^(N4)            are —CO—NH₂, —CO—NH(CH₃), or —CO—NH(C₂H₅));        -   —NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6) independently            represent hydrogen or (C₁₋₄)alkyl (wherein preferably at            least one of R^(N5) and R^(N6) represents hydrogen; and            wherein particular examples of such group            —NH—CO—NR^(N5)R^(N6) are —NH—CO—NH₂, —NH—CO—NH—C₂H₅);        -   —(CH₂)_(q)-HET¹, wherein q represents the integer 0, 1 or 2            (especially q is 0, i.e. HET¹ is linked to Ar¹ by a direct            bond); and wherein HET¹ represents            5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or            3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its            tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl);        -   HET, wherein HET represents a 5-membered heteroaryl            (especially oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,            isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,            triazolyl, or tetrazolyl), wherein said 5-membered            heteroaryl is unsubstituted, or mono- or di-substituted,            wherein the substituents are independently selected from            (C₁₋₄)alkyl (especially methyl), (C₁₋₄)alkoxy (especially            methoxy), —COOH, hydroxy, hydroxy-(C₁₋₃)alkyl (especially            hydroxymethyl), (C₃₋₅)cycloalkyl optionally containing one            ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or            —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently            represent hydrogen, (C₁₋₃)alkyl (especially methyl), or            hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);            (especially such group HET is 1H-tetrazol-5-yl,            3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl,            3-amino-isoxazol-5-yl, 2-amino-oxazol-5-yl,            5-amino-[1,3,4]thiadiazol-2-yl,            5-methylamino-[1,3,4]thiadiazol-2-yl,            5-methoxy-[1,2,4]oxadiazol-3-yl,            5-amino-[1,2,4]oxadiazol-3-yl,            5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,            5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,            5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,            5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl);

    -   R^(m1) represents        -   hydrogen;        -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl, isopropyl,            n-butyl, isobutyl);        -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,            isopropoxy, n-butoxy, isobutoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,            trifluoromethoxy, 2,2,2-trifluoroethoxy);        -   halogen (especially fluoro or chloro);        -   (C₃₋₆)cycloalkyl (especially cyclopropyl);        -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,            cyclobutyl-oxy, cyclopentyl-oxy);        -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);        -   —X²—NR^(N1)R^(N2), wherein X² represents a direct bond; or            X² represents —O—CH₂—CH₂₋*, wherein the asterisk indicates            the bond that is linked to the —NR^(N1)R^(N2) group; and            wherein R^(N1) and R^(N2) independently represent hydrogen,            (C₁₋₄)alkyl (especially methyl), or (C₃₋₆)cycloalkyl            (especially cyclopropyl); (especially such group            —X²—NR^(N1)R^(N2) represents amino, methylamino, ethylamino,            propylamino; or 2-(dimethylamino)-ethoxy);        -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl (especially            methyl, ethyl, n-propyl, isopropyl, isobutyl),            (C₃₋₆)cycloalkyl optionally containing one ring oxygen atom            (especially cyclobutyl, oxetan-3-yl);

    -   wherein in a sub-embodiment, R^(m1) especially is different from        hydrogen;

    -   R^(m2) represents hydrogen, methyl, fluoro, or chloro; and

    -   R^(o1) represents hydrogen; or, in case R^(m2) represents        hydrogen, R^(o1) represents hydrogen or fluoro;

    -   or Ar¹ represents a 5-membered heteroaryl group of the structure        (Ar-III):

-   -   wherein        -   Y represents CR⁸ wherein R⁸ represents especially hydrogen,            or halogen (notably fluoro, chloro); or Y represents N;        -   R⁷ represents            -   —X¹—CO—R^(O1), wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂—*,                    —NH—CH(CH₃)—*), —CH═CH—, —NH—CO—*, or                    (C₃₋₅)cycloalkylene; wherein the asterisks indicate                    the bond that is linked to the —CO—R^(O1) group; and                -   R^(O1) represents                -   —OH;                -   —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -   —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;                -   —O—CH₂—CO—R^(O4), wherein R^(O4) represents hydroxy,                    or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂;                -   —O—CH₂—O—CO—R⁵, wherein R^(O5) represents                    (C₁₋₄)alkyl or (C₁₋₄)alkoxy;                -   —O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ (especially                    —O—CH₂—CH₂—N(CH₃)₂); or                -   (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH,                —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CO—O—CH₂—COOH, —CO—O—CH₂—CH₂—N(CH₃)₂,                —CO—O—CH₂—CO—N(CH₃)₂, —CO—O—CH₂—O—CO—O—C₂H₅,                —CO—O—CH₂—O—CO-propyl,                (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—,                —CH₂—COOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—COOH,                —CH═CH—COOH, —NH—CO—COOH, 1-carboxy-cyclopropan-1-yl];

-   -   -   —CO—NR^(N3)R^(N4) wherein R^(N3) and R^(N4) independently            represent hydrogen, or (C₁₋₄)alkyl (wherein preferably at            least one of R^(N3) and R^(N4) represents hydrogen; and            wherein particular examples of such group —CO—NR^(N3)R^(N4)            are —CO—NH₂, —CO—NH(CH₃), —CO—NH(C₂H₅));        -   —NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6) independently            represent hydrogen or (C₁₋₄)alkyl (wherein preferably at            least one of R^(N5) and R^(N6) represents hydrogen; and            wherein particular examples of such group            —NH—CO—NR^(N5)R^(N6) are —NH—CO—NH₂, —NH—CO—NH—C₂H₅);        -   —(CH₂)_(q)-HET¹, wherein q represents the integer 0, 1 or 2            (especially q is 0, i.e. HET¹ is linked to Ar by a direct            bond); and wherein HET¹ represents            5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or            3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its            tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl);        -   HET, wherein HET represents a 5-membered heteroaryl            (especially oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,            isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,            triazolyl, or tetrazolyl), wherein said 5-membered            heteroaryl is unsubstituted, or mono- or di-substituted,            wherein the substituents are independently selected from            (C₁₋₄)alkyl (especially methyl), (C₁₋₄)alkoxy (especially            methoxy), —COOH, hydroxy, hydroxy-(C₁₋₃)alkyl (especially            hydroxymethyl), (C₃₋₅)cycloalkyl optionally containing one            ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or            —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently            represent hydrogen, (C₁₋₃)alkyl (especially methyl), or            hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);            (especially such group HET is 1H-tetrazol-5-yl,            3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl,            3-amino-isoxazol-5-yl, 2-amino-oxazol-5-yl,            5-amino-[1,3,4]thiadiazol-2-yl,            5-methylamino-[1,3,4]thiadiazol-2-yl,            5-methoxy-[1,2,4]oxadiazol-3-yl,            5-amino-[1,2,4]oxadiazol-3-yl,            5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,            5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,            5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,            5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl);

    -   R⁶ represents        -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl, isopropyl,            n-butyl, isobutyl);        -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,            isopropoxy, n-butoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,            trifluoromethoxy, 2,2,2-trifluoroethoxy);        -   halogen (especially fluoro or chloro);        -   (C₃₋₆)cycloalkyl (especially cyclopropyl);        -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,            cyclobutyl-oxy, cyclopentyl-oxy);        -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);        -   —X²—NR^(N1)R^(N2), wherein X² represents a direct bond; or            X² represents —O—CH₂—CH₂—*, wherein the asterisk indicates            the bond that is linked to the —NR^(N1)R^(N2) group; and            wherein R^(N1) and R^(N2) independently represent hydrogen,            (C₁₋₄)alkyl, or (C₃₋₆)cycloalkyl; (especially such group            —X²—NR^(N1)R^(N2) represents amino, methylamino, ethylamino,            propylamino; or 2-(dimethylamino)-ethoxy);        -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl (especially            methyl, ethyl, n-propyl, isopropyl, isobutyl),            (C₃₋₆)cycloalkyl optionally containing one ring oxygen atom            (especially cyclobutyl, oxetan-3-yl);

    -   or Ar¹ represents 8- to 10-membered bicyclic heteroaryl (notably        9- or 10-membered bicyclic heteroaryl; especially indazolyl,        benzoimidazolyl, indolyl, benzofuranyl, benzooxazolyl,        quinoxalinyl, isoquinolinyl, or quinolinyl); wherein said 8- to        10-membered bicyclic heteroaryl independently is        mono-substituted with —(C₀₋₃)alkylene-COOR² wherein R^(O2)        represents hydrogen or (C₁₋₄)alkyl (especially methyl) (wherein        especially such group —(C₀₋₃)alkylene-COOR^(O2) is —COOH);        (especially such 8- to 10-membered bicyclic heteroaryl is        3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl,        5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl,        7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl,        6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl,        3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or        2-carboxy-benzofuran-6-yl);

    -   or Ar¹ represents a group of the structure (Ar-III):

-   -   which is selected from 2-oxo-2,3-dihydro-benzooxazol-6-yl,        3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,        1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,        2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, and        1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl.        wherein in a sub-embodiment, Ar¹ especially is a phenyl group of        the structure (Ar-I) (wherein in particular R^(m1) especially is        different from hydrogen), or a 5-membered heteroaryl group of        the structure (Ar-III), as defined herein above.        6) Another embodiment relates to compounds defined in embodiment        4), for use according to embodiment 1), wherein Ar¹ represents

-   (i) a phenyl group of the structure (Ar-I):

-   -   wherein        -   R^(p) represents            -   (C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein                said (C₄₋₆)cycloalkyl containing a ring oxygen atom is                unsubstituted or mono-substituted with hydroxy                (especially 3-hydroxy-oxetan-3-yl);            -   hydroxy;            -   —X¹—CO—R¹, wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂—*,                    —NH—CH(CH₃)—*), —CH═CH—, —NH—CO—*, or                    (C₃₋₅)cycloalkylene; wherein the asterisks indicate                    the bond that is linked to the —CO—R^(O1) group; and                -   R^(O1) represents                -   —OH;                -   —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -   —NH—SO₂—R³ wherein R^(S3) represents (C₁₋₄)alkyl,                    (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl                    optionally contains a ring oxygen atom,                    (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, or —NH₂;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CH₂—COOH, —CH₂—CO—O—CH₃, CH₂—CO—O—C₂H₅, —CH(CH₃)—COOH,                —CH₂—CH₂—COOH, —CH═CH—COOH, —NH—CO—COOH,                —NH—CH(CH₃)—COOH, —NH—CH₂—CO—O—CH₃,                1-carboxy-cyclopropan-1-yl];

-   -   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;        -   —CO—NR^(N3)R^(N4) wherein R^(N3) and R^(N4) independently            represent hydrogen, or (C₁₋₄)alkyl, (wherein preferably at            least one of R^(N3) and R^(N4) represents hydrogen; and            wherein particular examples of such group —CO—NR^(N3)R^(N4)            are —CO—NH₂, —CO—NH(CH₃), or —CO—NH(C₂H₅));        -   —NH—CO—NR^(N)R^(N6) wherein R^(N5) and R^(N6) independently            represent hydrogen or (C₁₋₄)alkyl (wherein preferably at            least one of R^(N5) and R^(N6) represents hydrogen; and            wherein particular examples of such group            —NH—CO—NR^(N5)R^(N6) are —NH—CO—NH₂, —NH—CO—NH—C₂H₅);        -   HET¹, wherein HET¹ represents            5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or            3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its            tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl);        -   HET, wherein HET represents a 5-membered heteroaryl selected            from oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,            isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,            triazolyl, and tetrazolyl, wherein said 5-membered            heteroaryl is unsubstituted, or mono- or di-substituted,            wherein the substituents are independently selected from            (C₁₋₄)alkyl (especially methyl), (C₁₋₄)alkoxy (especially            methoxy), —COOH, hydroxy, hydroxy-(C₁₋₃)alkyl (especially            hydroxymethyl), (C₃₋₅)cycloalkyl optionally containing one            ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or            —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently            represent hydrogen, (C₁₋₃)alkyl (especially methyl), or            hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);            [especially such group HET is 1H-tetrazol-5-yl,            3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl,            3-amino-isoxazol-5-yl, 2-amino-oxazol-5-yl,            5-amino-[1,3,4]thiadiazol-2-yl,            5-methylamino-[1,3,4]thiadiazol-2-yl, 1H-imidazol-4-yl,            5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl; in            particular HET is 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl,            2-hydroxy-[1,3,4]oxadiazol-4-yl, or            5-amino-[1,3,4]thiadiazol-2-yl];

    -   R^(m1) represents        -   hydrogen;        -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl, isopropyl,            n-butyl, isobutyl);        -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,            isopropoxy, n-butoxy, isobutoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,            trifluoromethoxy, 2,2,2-trifluoroethoxy);        -   halogen (especially fluoro or chloro);        -   (C₃₋₆)cycloalkyl (especially cyclopropyl);        -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,            cyclobutyl-oxy, cyclopentyl-oxy);        -   hydroxy;        -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);        -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl (especially            methyl, ethyl, n-propyl, isopropyl, isobutyl),            (C₃₋₆)cycloalkyl optionally containing one ring oxygen atom            (especially cyclobutyl, oxetan-3-yl);        -   wherein in a sub-embodiment, R^(m1) especially is different            from hydrogen;

    -   R^(m2) represents hydrogen, methyl, fluoro, or chloro; and

    -   R^(o1) represents hydrogen;

-   (ii) or Ar¹ represents a 5-membered heteroaryl group of the    structure (Ar-III):

-   -   wherein        -   Y represents CH or N;        -   R⁷ represents            -   —X¹—CO—R¹, wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂—*,                    —NH—CH(CH₃)—*), —CH═CH—, —NH—CO—*, or                    (C₃₋₅)cycloalkylene; wherein the asterisks indicate                    the bond that is linked to the —CO—R^(O1) group; and                -   R^(O1) represents                -   —OH;                -   —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -   —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CH₂—COOH, —CH₂—CO—O—CH₃, CH₂—CO—O—C₂H₅, —CH(CH₃)—COOH,                —CH₂—CH₂—COOH, —CH═CH—COOH, —NH—CO—COOH,                —NH—CH(CH₃)—COOH, —NH—CH₂—CO—O—CH₃,                1-carboxy-cyclopropan-1-yl];

-   -   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;        -   —CO—NR^(N3)R^(N4) wherein R^(N3) and R^(N4) independently            represent hydrogen, or (C₁₋₄)alkyl (wherein preferably at            least one of R^(N3) and R^(N4) represents hydrogen; and            wherein particular examples of such group —CO—NR^(N3)R^(N4)            are —CO—NH₂, —CO—NH(CH₃), or —CO—NH(C₂H₅);        -   —NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6) independently            represent hydrogen or (C₁₋₄)alkyl (wherein preferably at            least one of R^(N5) and R^(N6) represents hydrogen; and            wherein particular examples of such group            —NH—CO—NR^(N5)R^(N6) are —NH—CO—NH₂, —NH—CO—NH—C₂H₅);        -   —(CH₂)_(q)-HET¹, wherein q represents the integer 0, 1 or 2            (especially q is 0, i.e. HET¹ is linked to Ar¹ by a direct            bond); and wherein HET¹ represents            5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl),            3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its            tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl);        -   —(CH₂)_(p)-HET, wherein p represents the integer 0 or 1            (especially p is 0, i.e. HET is linked to Ar¹ by a direct            bond); and wherein HET represents a 5-membered heteroaryl            selected from oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,            isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,            triazolyl, and tetrazolyl, wherein said 5-membered            heteroaryl is unsubstituted, or mono- or di-substituted,            wherein the substituents are independently selected from            (C₁₋₄)alkyl (especially methyl), (C₁₋₄)alkoxy (especially            methoxy), —COOH, hydroxy, hydroxy-(C₁₋₃)alkyl (especially            hydroxymethyl), (C₃₋₅)cycloalkyl optionally containing one            ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or            —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently            represent hydrogen, (C₁₋₃)alkyl (especially methyl), or            hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);            [especially such group HET is 1H-tetrazol-5-yl,            3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl,            3-amino-isoxazol-5-yl, 2-amino-oxazol-5-yl,            5-amino-[1,3,4]thiadiazol-2-yl,            5-methylamino-[1,3,4]thiadiazol-2-yl, 1H-imidazol-4-yl,            5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl; in            particular HET is 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl,            2-hydroxy-[1,3,4]oxadiazol-4-yl, or            5-amino-[1,3,4]thiadiazol-2-yl];

    -   R⁶ represents        -   (C₁-)alkyl (especially methyl, ethyl, n-propyl, isopropyl,            n-butyl, isobutyl);        -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,            isopropoxy, n-butoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,            trifluoromethoxy, 2,2,2-trifluoroethoxy);        -   halogen (especially fluoro or chloro);        -   hydroxy;        -   (C₃₋₆)cycloalkyl (especially cyclopropyl);        -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,            cyclobutyl-oxy, cyclopentyl-oxy);        -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);        -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl (especially            methyl, ethyl, n-propyl, isopropyl, isobutyl),            (C₃₋₆)cycloalkyl optionally containing one ring oxygen atom            (especially cyclobutyl, oxetan-3-yl);

-   (iii) or Ar¹ represents 3-carboxy-1H-indol-6-yl,    4-carboxy-1H-indol-2-yl, 5-carboxy-1H-indol-2-yl,    6-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-2-yl,    5-(methoxycarbonyl)-1H-indol-2-yl,    6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl,    3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or    2-carboxy-benzofuran-6-yl;

-   (iv) or Ar¹ represents a group of the structure (Ar-III):

-   -   wherein ring (B) represents 2-oxo-2,3-dihydro-benzooxazol-6-yl,        3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,        1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,        2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, or        1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl;        wherein in a sub-embodiment, Ar¹ especially is a phenyl group of        the structure (Ar-I) (wherein in particular R^(m1) especially is        different from hydrogen), or a 5-membered heteroaryl group of        the structure (Ar-II), as defined herein above.        7) Another embodiment relates to compounds defined in embodiment        4), for use according to embodiment 1), wherein Ar¹ represents a        group selected from:

A)

or, in addition, Ar¹ represents a group selected from:

B)

wherein each of the groups A) and B) forms a particular sub-embodiment;wherein in a further sub-embodiment, Ar¹ especially is a phenyl group(in particular a di-substituted phenyl group), or a thiophenyl group, ora thiazolyl group, as defined in groups A) and/or B) herein above.8) Another embodiment relates to compounds defined in embodiment 4), foruse according to embodiment 1), wherein

-   (i) Ar¹ represents a phenyl group selected from:

-   (ii) or Ar¹ represents a thiophenyl group selected from:

-   (iii) or Ar¹ represents a thiazolyl group selected from:

-   (iv) or Ar¹ represents 9- or 10-membered bicyclic heteroaryl    selected from

-   (v) or Ar¹ represents a group selected from:

wherein in a sub-embodiment, Ar¹ especially is a phenyl group (inparticular a di-substituted phenyl group), or a thiophenyl group, or athiazolyl group, as defined herein above.9) Another embodiment relates to compounds defined in embodiment 4), foruse according to embodiment 1), wherein

-   (i) Ar¹ represents a phenyl group selected from:    -   a)

-   -   b)

-   -   c)

-   -   d)

-   -   wherein in the above groups di-substituted phenyl groups are        preferred groups.

-   (ii) or Ar¹ represents a thiophenyl group selected from:    -   a)

-   -   b)

-   -   c)

-   -   d)

-   -   e)

-   (iii) or Ar¹ represents a thiazolyl group selected from:    -   a)

-   -   b)

-   (iv) or Ar¹ represents 9- or 10-membered bicyclic heteroaryl    selected from    -   a)

-   -   b)

-   (v) or Ar¹ represents a group selected from:

wherein in a sub-embodiment, Ar¹ especially is a phenyl group (inparticular a di-substituted phenyl group), or a thiophenyl group, or athiazolyl group, as defined herein above.10) A second embodiment relates to compounds as defined in any one ofembodiments 1) to 9), for use according to embodiment 1), wherein R³represents hydrogen.11) Another embodiment relates to compounds as defined in any one ofembodiments 1) to 9), for use according to embodiment 1), wherein R³represents methyl.12) Another embodiment relates to compounds as defined in any one ofembodiments 1) to 9), wherein the characteristics defined for thefragment

according to embodiments 14), or 16) to 20) below apply mutatismutandis.13) Another embodiment relates to compounds as defined in any one ofembodiments 1) to 9), wherein the characteristics defined for thesubstituent Ar¹ according to embodiments 14) or 15) below apply mutatismutandis.14) A third aspect of the invention relates to novel compounds of theformula (III)

wherein in compounds of the formula (III), ring (A) in the fragment:

represents an aromatic 5- or 6-membered ring or a non-aromatic 5- or6-membered ring, which ring (A) is fused to the phenyl group, whereinindependently said ring (A) optionally contains one or two heteroatomsindependently selected from nitrogen, oxygen, and sulfur (notably suchfused group is benzofuranyl, benzothiophenyl, benzothiazolyl,benzoisothiazolyl, indolyl, indazolyl, naphthyl, quinolinyl,isoquinolinyl, 2,3-dihydro-benzo[b]thiophenyl, benzo[1,3]dioxolyl,1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, indanyl,5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,1,2,3,4-tetrahydro-quinolinyl);wherein said fragment is optionally substituted with (R¹)_(n); wherein(R¹)_(n) represents one, two, three, or four optional substituents (i.e.said fragment is unsubstituted, or substituted with one, two, three, orfour R¹), wherein said substituents R¹ are independently selected from(C₁₋₃)alkyl (especially methyl), (C₂₋₃)alkenyl (especially vinyl),(C₂₋₃)alkynyl (especially ethynyl), (C₁₋₃)alkoxy (especially methoxy,ethoxy, isopropoxy), halogen (especially fluoro, or chloro),—S—(C₁₋₃)alkyl (especially methylsulfanyl), (C₁₋₃)fluoroalkyl(especially trifluoromethyl), (C₁₋₃)fluoroalkoxy (especiallytrifluoromethoxy, difluoromethoxy), cyano, oxo, or amino;and Ar¹ represents

-   -   a phenyl group of the structure (Ar-I):

-   -   wherein        -   R^(p) represents            -   —X¹—CO—R¹, wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂—*,                    —NH—CH(CH₃)—*), —CH═CH—, —NH—CO—*, or                    (C₃₋₅)cycloalkylene; wherein the asterisks indicate                    the bond that is linked to the —CO—R^(O1) group; and                -   R^(O1) represents                -   —OH;                -   —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -   —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH,                —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CH₂—COOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—COOH,                —CH═CH—COOH, —NH—CO—COOH, 1-carboxy-cyclopropan-1-yl];        -   HET¹, wherein HET¹ represents            5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or            3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its            tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl); or        -   HET, wherein HET represents a group selected from            1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl,            2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl,            2-amino-oxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl,            5-methylamino-[1,3,4]thiadiazol-2-yl,            5-amino-[1,2,4]oxadiazol-3-yl; especially HET is            1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl, or            2-hydroxy-[1,3,4]oxadiazol-4-yl;    -   R^(m1) represents        -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl, isopropyl,            n-butyl, isobutyl);        -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,            isopropoxy, n-butoxy, isobutoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,            trifluoromethoxy, 2,2,2-trifluoroethoxy);        -   halogen (especially fluoro or chloro);        -   (C₃₋₆)cycloalkyl (especially cyclopropyl);        -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,            cyclobutyl-oxy, cyclopentyl-oxy);        -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy); or        -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl (especially            methyl, ethyl, n-propyl, isopropyl, isobutyl),            (C₃₋₆)cycloalkyl optionally containing one ring oxygen atom            (especially cyclobutyl, oxetan-3-yl);    -   R^(m2) represents hydrogen, methyl, fluoro, or chloro; and    -   R^(o1) represents hydrogen;    -   or Ar¹ represents a 5-membered heteroaryl group of the structure        (Ar-III):

-   -   wherein        -   Y represents CH or N;        -   R⁷ represents            -   —X¹—CO—R^(O1), wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂—*,                    —NH—CH(CH₃)—*), —CH═CH—, —NH—CO—*, or                    (C₃₋₅)cycloalkylene; wherein the asterisks indicate                    the bond that is linked to the —CO—R^(O1) group; and                -   R^(O1) represents                -   —OH;                -   —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -   —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;        -   [wherein in particular such group —X¹—CO—R^(O1) represents            —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH, —O—CH(CH₃)—COOH,            —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH, —NH—CH₂—COOH,            —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH, —CO—NH—SO₂—CH₃,            —CO—NH—SO₂—C(CH₃)₂, —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅,            —CO—NH—SO₂—NH₂, —CH₂—COOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅,            —CH₂—CH₂—COOH, —CH═CH—COOH, —NH—CO—COOH,            1-carboxy-cyclopropan-1-yl];        -   HET¹, wherein HET¹ represents            5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or            3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its            tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl); or        -   HET, wherein HET represents a group selected from            1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl,            2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl,            2-amino-oxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl,            5-methylamino-[1,3,4]thiadiazol-2-yl,            5-amino-[1,2,4]oxadiazol-3-yl; especially HET is            1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl, or            2-hydroxy-[1,3,4]oxadiazol-4-yl;    -   R⁶ represents        -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl, isopropyl,            n-butyl, isobutyl);        -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,            isopropoxy, n-butoxy);        -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);        -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,            trifluoromethoxy, 2,2,2-trifluoroethoxy);        -   halogen (especially fluoro or chloro);        -   (C₃₋₆)cycloalkyl (especially cyclopropyl);        -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,            cyclobutyl-oxy, cyclopentyl-oxy);        -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy); or        -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl (especially            methyl, ethyl, n-propyl, isopropyl, isobutyl),            (C₃₋₆)cycloalkyl optionally containing one ring oxygen atom            (especially cyclobutyl, oxetan-3-yl).            15) Another embodiment relates to compounds as defined in            any one of embodiments 1) to 13), for use according to            embodiment 1), and to compounds according to embodiment 14),            wherein Ar¹ represents a group selected from

16) Another embodiment relates to compounds as defined in any one ofembodiments 1) to 13), for use according to embodiment 1), and tocompounds according to embodiments 14) or 15), wherein in the fragment

-   -   ring (A) represents an aromatic 5- or 6-membered ring fused to        the phenyl group, wherein said ring (A) optionally contains one        or two heteroatoms independently selected from nitrogen, oxygen,        and sulfur (notably such fused group is benzofuranyl,        benzothiophenyl, benzothiazolyl, benzoisothiazolyl, indolyl,        indazolyl, naphthyl, quinolinyl, isoquinolinyl); wherein said        fragment is optionally substituted with (R¹)_(n); wherein        (R¹)_(n) represents one, two, three, or four optional        substituents (i.e. said fragment is unsubstituted, or        substituted with one, two, three, or four R¹), wherein said        substituents R¹ are independently selected from (C₁₋₃)alkyl        (especially methyl), (C₁₋₃)alkoxy (especially methoxy, ethoxy,        n-propoxy, isopropoxy), halogen (especially fluoro, chloro,        bromo), (C₁₋₃)fluoroalkyl (especially difluoromethyl,        trifluoromethyl), (C₁₋₃)fluoroalkoxy (especially        trifluoromethoxy, difluoromethoxy), cyano, or amino;    -   or ring (A) represents a non-aromatic 5- or 6-membered ring        fused to the phenyl group, wherein said ring (A) optionally        contains one or two heteroatoms independently selected from        nitrogen, oxygen, and sulfur (notably such fused group is        2,3-dihydro-benzo[b]thiophenyl, benzo[1,3]dioxolyl,        1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, indanyl,        5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,        chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,        1,2,3,4-tetrahydro-quinolinyl; especially benzo[1,3]dioxolyl,        1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl,        1,2,3,4-tetrahydro-quinolinyl); wherein said fragment is        optionally substituted with (R¹)_(n); wherein (R¹)_(n)        represents one, two, or three optional substituents (i.e. said        fragment is unsubstituted, or substituted with one, two, or        three R¹), wherein said substituents R¹ are independently        selected from (C₁₋₃)alkyl (especially methyl), (C₁₋₃)alkoxy        (especially methoxy, ethoxy, n-propoxy, isopropoxy), halogen        (especially fluoro, or chloro), (C₁₋₃)fluoroalkyl (especially        trifluoromethyl), (C₁₋₃)fluoroalkoxy (especially        trifluoromethoxy, difluoromethoxy), or oxo (in particular        (C₁₋₃)alkyl or (C₁₋₃)alkoxy).        17) Another embodiment relates to compounds as defined in any        one of embodiments 1) to 13), for use according to embodiment        1), and to compounds according to embodiments 14) or 15),        wherein the fragment

represents

-   -   a group selected from benzofuranyl, benzothiophenyl,        benzothiazolyl, benzoisothiazolyl, indolyl, indazolyl, naphthyl,        quinolinyl, and isoquinolinyl; which group independently is        unsubstituted or substituted with (R¹)_(n); wherein (R¹)_(n)        represents one, two, or three substituents, wherein said        substituents R¹ are independently selected from (C₁₋₃)alkyl        (especially methyl), (C₁₋₃)alkoxy (especially methoxy, ethoxy,        n-propoxy, isopropoxy), halogen (especially fluoro, chloro,        bromo), (C₁₋₃)fluoroalkyl (especially difluoromethyl,        trifluoromethyl), (C₁₋₃)fluoroalkoxy (especially        trifluoromethoxy, difluoromethoxy), cyano, or amino; or    -   a group selected from 2,3-dihydro-benzo[b]thiophenyl,        benzo[1,3]dioxolyl, 1,3-dihydro-isobenzofuranyl,        2,3-dihydro-benzofuranyl, indanyl,        5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,        chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,        1,2,3,4-tetrahydro-quinolinyl; especially benzo[1,3]dioxolyl,        1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl,        1,2,3,4-tetrahydro-quinolinyl (especially benzo[1,3]dioxolyl,        2,3-dihydro-benzofuranyl, 1,2,3,4-tetrahydro-quinolinyl); which        group independently is unsubstituted, or substituted with        (R¹)_(n); wherein (R¹)_(n) represents one, two, or three        substituents, wherein said substituents R¹ are independently        selected from (C₁₋₃)alkyl (especially methyl), (C₁₋₃)alkoxy        (especially methoxy, ethoxy, n-propoxy, isopropoxy), halogen        (especially fluoro, or chloro), (C₁₋₃)fluoroalkyl (especially        trifluoromethyl), (C₁₋₃)fluoroalkoxy (especially        trifluoromethoxy, difluoromethoxy), or oxo (in particular        (C₁₋₃)alkyl or (C₁₋₃)alkoxy).        18) Another embodiment relates to compounds as defined in any        one of embodiments 1) to 13), for use according to embodiment        1), and to compounds according to embodiments 14) or 15),        wherein the fragment

represents a group selected from the following groups a), b), c), andd):

-   a) benzothiophen-7-yl, benzothiophen-4-yl,    2-methyl-benzothiazol-7-yl, benzofuran-7-yl, benzofuran-4-yl,    2-methyl-benzofuran-7-yl, 1H-indol-7-yl, 1H-indol-4-yl,    2-methyl-1H-indol-7-yl, 1-methyl-1H-indol-7-yl,    1-methyl-1H-indol-4-yl, 1,2-dimethyl-1H-indol-7-yl,    1,2,3-trimethyl-1H-indol-7-yl, 1,5-dimethyl-1H-indazol-4-yl;-   b) benzo[1,3]dioxol-4-yl, 5-methoxy-benzo[1,3]dioxol-4-yl,    5-ethoxy-benzo[1,3]dioxol-4-yl,    5-methoxy-2,3-dihydro-benzofuran-4-yl,    6-methoxy-1-methyl-1,2,3,4-tetrahydro-quinolin-5-yl;-   c) naphthalen-1-yl, 4-chloro-naphthalen-1-yl,    4-fluoro-naphthalen-1-yl, 2-fluoro-naphthalen-1-yl,    2-bromo-naphthalen-1-yl, 2-methyl-naphthalen-1-yl,    4-methyl-naphthalen-1-yl, 2-amino-naphthalen-1-yl,    2,3-dimethyl-naphthalen-1-yl, 2-methoxy-naphthalen-1-yl,    3-methoxy-naphthalen-1-yl, 4-methoxy-naphthalen-1-yl,    2-cyano-naphthalen-1-yl, 4-cyano-naphthalen-1-yl,    4-difluoromethyl-naphthalen-1-yl, 2-difluoromethyl-naphthalen-1-yl,    2-ethoxy-naphthalen-1-yl, 2,5-dimethoxy-naphthalen-1-yl,    2,3-dimethoxy-naphthalen-1-yl, 2-n-propoxy-naphthalen-1-yl,    2-isopropoxy-naphthalen-1-yl, 2-difluoromethoxy-naphthalen-1-yl; and-   d) quinolin-8-yl, 7-chloro-quinolin-8-yl, 6-methyl-quinolin-5-yl,    7-methoxy-quinolin-8-yl, 6-methoxy-quinolin-5-yl,    2-methoxy-quinolin-8-yl, 6-fluoro-2-methoxy-quinolin-8-yl,    5-fluoro-2-methoxy-quinolin-8-yl, 7-fluoro-2-methoxy-quinolin-8-yl,    7-methoxy-4-methyl-quinolin-8-yl, 6-methoxy-2-methyl-quinolin-5-yl,    isoquinolin-8-yl, isoquinolin-5-yl, 6-methyl-isoquinolin-5-yl;    or said fragment represents a group selected from the following    groups e), f) and g)-   e) 6-fluoro-benzo[b]thiophen-4-yl, 5-methoxy-benzo[b]thiophen-4-yl,    4-bromo-1-methyl-1H-indol-7-yl, 1,5-dimethyl-1H-indol-4-yl,    5-ethoxy-benzo[b]thiophen-4-yl, 6-methoxy-1-methyl-1H-indol-7-yl,    5-methoxy-1-methyl-1H-indol-4-yl;-   f) 5-fluoro-naphthalen-1-yl, 3-fluoro-naphthalen-1-yl,    4-bromo-naphthalen-1-yl, 5-methyl-naphthalen-1-yl,    2-bromo-4-fluoro-naphthalen-1-yl,    2-cyano-8-fluoro-5-methoxy-naphthalen-1-yl; and-   g) quinolin-5-yl;    wherein the groups a) to d) together, and the groups e) to g)    together each form a particular sub-embodiment.    19) Another embodiment relates to compounds as defined in any one of    embodiments 1) to 13), for use according to embodiment 1), and to    compounds according to embodiments 14) or 15), wherein the fragment

representsrepresents a group selected from the following groups a), b), c), andd):

-   a) benzothiophen-7-yl, benzothiophen-4-yl,    benzofuran-7-yl2-methyl-benzofuran-7-yl, 1H-indol-4-yl,    1-methyl-1H-indol-7-yl, 1-methyl-1H-indol-4-yl,    1,5-dimethyl-1H-indazol-4-yl;-   b) 5-ethoxy-benzo[1,3]dioxol-4-yl,    5-methoxy-2,3-dihydro-benzofuran-4-yl;-   c) naphthalen-1-yl, 4-chloro-naphthalen-1-yl,    4-fluoro-naphthalen-1-yl, 2-fluoro-naphthalen-1-yl,    2-bromo-naphthalen-1-yl, 2-methyl-naphthalen-1-yl,    4-methyl-naphthalen-1-yl, 2-amino-naphthalen-1-yl,    2,3-dimethyl-naphthalen-1-yl, 2-methoxy-naphthalen-1-yl,    3-methoxy-naphthalen-1-yl, 4-methoxy-naphthalen-1-yl,    2-cyano-naphthalen-1-yl, 4-cyano-naphthalen-1-yl,    4-difluoromethyl-naphthalen-1-yl, 2-ethoxy-naphthalen-1-yl,    2,3-dimethoxy-naphthalen-1-yl, 2-n-propoxy-naphthalen-1-yl,    2-isopropoxy-naphthalen-1-yl, 2-difluoromethoxy-naphthalen-1-yl;-   d) 6-methyl-quinolin-5-yl, 6-methoxy-quinolin-5-yl,    isoquinolin-5-yl.    20) The invention, thus, relates to compounds of the formula (I) as    defined in embodiment 1) for use according to embodiment 1), or to    such compounds further limited by the characteristics of any one of    embodiments 2) to 19), under consideration of their respective    dependencies; to pharmaceutically acceptable salts thereof; and to    the use of such compounds according to embodiment 1), and as further    described herein below. For avoidance of any doubt, especially the    following embodiments relating to the compounds of formula (I) are    thus possible and intended and herewith specifically disclosed in    individualized form:    1, 4+1, 5+4+1, 6+4+1, 7+4+1, 8+4+1, 9+4+1, 10+4+1, 10+5+4+1,    10+6+4+1, 10+7+4+1, 10+8+4+1, 10+9+4+1, 16+4+1, 16+5+4+1, 16+6+4+1,    16+7+4+1, 16+8+4+1, 16+9+4+1, 16+10+4+1, 16+10+5+4+1, 16+10+6+4+1,    16+10+7+4+1, 16+10+8+4+1, 16+10+9+4+1, 17+4+1, 17+5+4+1, 17+6+4+1,    17+7+4+1, 17+8+4+1, 17+9+4+1, 17+10+4+1, 17+10+5+4+1, 17+10+6+4+1,    17+10+7+4+1, 17+10+8+4+1, 17+10+9+4+1, 18+4+1, 18+5+4+1, 18+6+4+1,    18+7+4+1, 18+8+4+1, 18+9+4+1, 18+10+4+1, 18+10+5+4+1, 18+10+6+4+1,    18+10+7+4+1, 18+10+8+4+1, 18+10+9+4+1, 19+4+1, 19+5+4+1, 19+6+4+1,    19+7+4+1, 19+8+4+1, 19+9+4+1, 19+10+4+1, 19+10+5+4+1, 19+10+6+4+1,    19+10+7+4+1, 19+10+8+4+1, 19+10+9+4+1.

In the list above the numbers refer to the embodiments according totheir numbering provided hereinabove whereas “+” indicates thedependency from another embodiment. The different individualizedembodiments are separated by commas. In other words, “19+9+4+1” forexample refers to embodiment 19) depending on embodiment 9), dependingon embodiment 4), depending on embodiment 1), i.e. embodiment “19+9+4+1”corresponds to the compounds of formula (I) as defined in embodiment 1)for use according to embodiment 1), further limited by all thestructural features of the embodiments 4), 9), and 19).

21) The invention, thus, further relates to compounds of the formula(III) as defined in embodiment 14), or to such compounds further limitedby the characteristics of any one of embodiments 15) to 19), underconsideration of their respective dependencies; to pharmaceuticallyacceptable salts thereof; and to the use of such compounds asmedicaments especially in the prevention/prophylaxis or treatment ofdiseases which respond to the blockage of the EP2 receptors and/or theEP4 receptors as described herein below. For avoidance of any doubt,especially the following embodiments relating to the compounds offormula (III) are thus possible and intended and herewith specificallydisclosed in individualized form:14, 15+14, 16+14, 16+15+14, 17+14, 17+15+14, 18+14, 18+15+14, 19+14,19+15+14.

In the list above the numbers refer to the embodiments according totheir numbering provided hereinabove whereas “+” indicates thedependency from another embodiment. The different individualizedembodiments are separated by commas. In other words, “19+15+14” forexample refers to embodiment 19) depending on embodiment 15), dependingon embodiment 14), i.e. embodiment “19+15+14” corresponds to thecompounds of formula (III) according to embodiment 14) further limitedby all the features of the embodiments 15), and 19).

22) Another embodiment relates to compounds of formula (I) as defined inembodiment 1) for use according to embodiment 1) which are selected fromthe following compounds:

-   [2-(6-Methoxy-quinolin-5-yl)-ethyl]-[6-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-yl)-pyrimidin-4-yl]-amine;-   [2-(1,5-Dimethyl-1H-indazol-4-yl)-ethyl]-(6-quinolin-6-yl-pyrimidin-4-yl)-amine;    and-   [2-(1,5-Dimethyl-1H-indazol-4-yl)-ethyl]-(6-isoquinolin-7-yl-pyrimidin-4-yl)-amine.    23) Another embodiment relates to compounds of formula (II) as    defined in embodiment 4) which are selected from the following    compounds:-   3-Hydroxy-4-(4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-cyclobut-3-ene-1,2-dione;-   2-{6-[2-(2-Methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-1H-indole-4-carboxylic    acid;-   2-{6-[2-(2-Methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-1H-indole-5-carboxylic    acid;-   2-{6-[2-(2-Methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-1H-indole-6-carboxylic    acid;-   5-(4-{6-[2-(6-Methoxy-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-isoxazol-3-ol    [tautomeric form:    5-(4-(6-((2-(6-methoxyquinolin-5-yl)ethyl)amino)pyrimidin-4-yl)phenyl)isoxazol-3(2H)-one];-   5-(4-{6-[2-(2-Methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-isoxazol-3-ol    [tautomeric form:    5-(4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)phenyl)isoxazol-3(2H)-one];-   2-Ethoxy-4-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-phenol;    and-   {6-[4-(5-Amino-[1,3,4]thiadiazol-2-yl)-phenyl]-pyrimidin-4-yl}-[2-(6-methoxy-quinolin-5-yl)-ethyl]-amine.    24) In addition to the compounds listed in embodiment 23), further    compounds of formula (II) as defined in embodiment 4), are selected    from the following compounds:-   3-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]-oxadiazole-5(4H)-thione    [tautomeric form:    3-(2-ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazole-5-thiol];    and-   3-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzyl)-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzyl)-[1,2,4]oxadiazol-5-ol].    25) Another embodiment relates to compounds of formula (III)    according to embodiment 14), which are selected from the following    compounds:-   3-Ethoxy-5-{6-[2-(2-methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-methyl-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-[6-(2-naphthalen-1-yl-ethylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic    acid;-   5-{6-[2-(2-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-{6-[2-(2,3-Dimethyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-methoxy-2-methyl-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(2,3-Dimethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-{6-[2-(7-Chloro-quinolin-8-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(4-methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(4-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(1-methyl-1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(1-methyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(2-ethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(1,2,3-trimethyl-1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(2-isopropoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(2-Difluoromethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid; acid;-   5-[6-(2-Benzofuran-7-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(2-propoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(3-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(5-methoxy-benzo[1,3]dioxol-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(5-ethoxy-benzo[1,3]dioxol-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(4-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(4-Chloro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(2-Cyano-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-{6-[2-(4-Cyano-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-{6-[2-(4-Difluoromethyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(2-methyl-benzofuran-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(2-Amino-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-{6-[2-(1,5-Dimethyl-1H-indazol-4-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-methyl-isoquinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(2-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-[6-(2-Benzo[b]thiophen-7-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   5-[6-(2-Benzo[b]thiophen-4-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   (E)-3-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acrylic    acid;-   2-Butoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(2-Methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoic    acid;-   {6-[3-Ethoxy-4-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-4-yl}-[2-(2-methoxy-naphthalen-1-yl)-ethyl]-amine;-   3-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-4H-[1,2,4]oxadiazol-5-one    [tautomeric form:    3-(2-ethoxy-4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-1,2,4-oxadiazol-5-ol];-   3-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-propionic    acid;-   N-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-oxalamic    acid;-   3-ethoxy-5-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)-N-sulfamoylthiophene-2-carboxamide;-   N-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbonyl)-methanesulfonamide;-   3-(3-Ethoxy-5-{6-[2-(1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(5-(6-((2-(1H-indol-4-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-1,2,4-oxadiazol-5-ol];-   3-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(3-ethoxy-5-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol];-   3-{3-Ethoxy-5-[6-(2-quinolin-8-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(3-ethoxy-5-(6-((2-(quinolin-8-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol];-   3-(3-Ethoxy-5-{6-[2-(4-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(3-ethoxy-5-(6-((2-(4-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol];-   3-(3-Ethoxy-5-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(3-ethoxy-5-(6-((2-(6-methoxyquinolin-5-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol];-   3-(3-Ethoxy-5-{6-[2-(1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(5-(6-((2-(1H-indol-7-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-1,2,4-oxadiazol-5-ol];-   3-{3-Ethoxy-5-[6-(2-isoquinolin-5-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(3-ethoxy-5-(6-((2-(isoquinolin-5-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol];-   {6-[4-Ethoxy-5-(1H-tetrazol-5-yl)-thiophen-2-yl]-pyrimidin-4-yl}-[2-(6-methoxy-quinolin-5-yl)-ethyl]-amine;    4-Ethoxy-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylic    acid;-   3-(4-Ethoxy-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(4-ethoxy-2-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)thiazol-5-yl)-1,2,4-oxadiazol-5-ol];-   5-{6-[2-(6-Methoxy-1-methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylic    acid;    3-(2-Hydroxy-ethoxy)-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid.    26) In addition to the compounds listed in embodiment 25), further    compounds of formula (III) according to embodiment 14), are selected    from the following compounds:-   2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethoxy-4-[6-(2-naphthalen-1-yl-ethylamino)-pyrimidin-4-yl]-benzoic    acid;-   4-{6-[2-(2-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic    acid;-   2-Ethoxy-4-{6-[2-(4-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(2-ethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   3-Ethoxy-5-{6-[2-(7-methoxy-quinolin-8-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(2-methyl-1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(1,2-Dimethyl-1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   2-Cyclobutoxy-4-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(2-Cyano-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic    acid;-   5-{6-[2-(6-Methoxy-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylic    acid;-   (2-Ethoxy-4-{6-[2-(6-methyl-isoquinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   2-Ethoxy-4-{6-[2-(2-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(2-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   3-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionic    acid;-   2-Isobutyl-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Fluoro-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-6-propyl-benzoic    acid;-   2-Butoxy-6-fluoro-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Difluoromethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acetic    acid;-   4-Ethyl-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylic    acid; and-   2-(2-Hydroxy-ethoxy)-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid.    27) In addition to the compounds listed in embodiments 25) and 26),    further compounds of formula (III) according to embodiment 14), are    selected from the following compounds:-   5-{6-[2-(2,5-Dimethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   2-Ethylsulfanyl-4-{6-[2-(4-methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid; and-   3-{3-Ethoxy-5-[6-(2-isoquinolin-8-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(3-ethoxy-5-(6-((2-(isoquinolin-8-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol].    28) In addition to the compounds listed in embodiments 25) to 27),    further compounds of formula (III) according to embodiment 14), are    selected from the following compounds:-   4-{6-[2-(4-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic    acid;-   5-{6-[2-(2-Cyano-8-fluoro-5-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   4-{6-[2-(6-Methoxy-1-methyl-1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   4-{6-[2-(4-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(5-methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   2-Ethoxy-4-{6-[2-(5-methoxy-benzo[b]thiophen-4-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   3-(4-Ethyl-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(4-ethyl-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5-ol];    and-   4-{6-[2-(5-Methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid.    29) In addition to the compounds listed in embodiments 25) to 28),    further compounds of formula (III) according to embodiment 14), are    selected from the following compounds:-   (2-Ethoxy-4-{6-[2-(5-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Ethoxy-4-{6-[2-(5-methoxy-1-methyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   2-Ethoxy-4-{6-[2-(5-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   3-{3-Ethoxy-5-[6-(2-quinolin-5-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5-ol    [tautomeric form:-   3-(3-ethoxy-5-(6-((2-(quinolin-5-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5(4H)-one];-   (2-Ethoxy-4-{6-[2-(5-methoxy-benzo[b]thiophen-4-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   4-{6-[2-(5-Fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(1-methyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethoxy-4-{6-[2-(5-methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   2-Ethoxy-4-{6-[2-(5-ethoxy-benzo[b]thiophen-4-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethoxy-4-{6-[2-(5-methoxy-1-methyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(5-Methoxy-benzo[b]thiophen-4-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   4-{6-[2-(5-Ethoxy-benzo[b]thiophen-4-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   2-Ethoxy-4-{6-[2-(2-ethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(1,5-Dimethyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid; and-   4-{6-[2-(5-Methoxy-1-methyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid.

The compounds of formulae (I), (II), or (III) according toembodiments 1) to 29) and their pharmaceutically acceptable salts can beused as medicaments, e.g. in the form of pharmaceutical compositions forenteral (such especially oral e.g. in form of a tablet or a capsule) orparenteral administration (including topical application or inhalation).

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see forexample Remington, The Science and Practice of Pharmacy, 21st Edition(2005), Part 5, “Pharmaceutical Manufacturing” [published by LippincottWilliams & Wilkins]) by bringing the described compounds of formulae(I), (II), or (III) or their pharmaceutically acceptable salts,optionally in combination with other therapeutically valuablesubstances, into a galenical administration form together with suitable,non-toxic, inert, therapeutically compatible solid or liquid carriermaterials and, if desired, usual pharmaceutical adjuvants.

The present invention also relates to a method for theprevention/prophylaxis or treatment of a disease or disorder mentionedherein comprising administering to a subject a pharmaceutically activeamount of a compound of formulae (I), (II), or (III) according toembodiments 1) to 29).

In a preferred embodiment of the invention, the administered amount iscomprised between 1 mg and 2000 mg per day, particularly between 5 mgand 1000 mg per day, more particularly between 25 mg and 500 mg per day,especially between 50 mg and 200 mg per day.

Whenever the word “between” is used to describe a numerical range, it isto be understood that the end points of the indicated range areexplicitly included in the range. For example: if a temperature range isdescribed to be between 40° C. and 80° C., this means that the endpoints 40° C. and 80° C. are included in the range; or if a variable isdefined as being an integer between 1 and 4, this means that thevariable is the integer 1, 2, 3, or 4.

Unless used regarding temperatures, the term “about” placed before anumerical value “X” refers in the current application to an intervalextending from X minus 10% of X to X plus 10% of X, and preferably to aninterval extending from X minus 5% of X to X plus 5% of X. In theparticular case of temperatures, the term “about” placed before atemperature “Y” refers in the current application to an intervalextending from the temperature Y minus 10° C. to Y plus 10° C., andpreferably to an interval extending from Y minus 5° C. to Y plus 5° C.

For avoidance of any doubt, if compounds are described as useful for theprevention/prophylaxis or treatment of certain diseases, such compoundsare likewise suitable for use in the preparation of a medicament for theprevention/prophylaxis or treatment of said diseases. Likewise, suchcompounds are also suitable in a method for the prevention/prophylaxisor treatment of such diseases, comprising administering to a subject(mammal, especially human) in need thereof, an effective amount of suchcompound.

The compounds of formulae (I), (II), or (III) according toembodiments 1) to 29) are useful for the prevention/prophylaxis ortreatment of disorders relating to the EP2 and/or EP4 receptors.

Certain compounds of formulae (I), (II), or (III) according toembodiments 1) to 29) exhibit their biological activity as modulators ofthe prostaglandin 2 receptors EP2 and/or EP4 in a biologicalenvironment, (i.e. in the presence of one or more enzymes capable ofbreaking a covalent bond linked to a carbonyl group such as an amidase,an esterase or any suitable equivalent thereof capable of removing aprodrug group from a carboxylic acid group.

Diseases or disorders relating to the EP2 and/or EP4 receptors areespecially

-   -   cancer (notably melanoma including metastatic melanoma; lung        cancer including non-small cell lung cancer; bladder cancer        including urinary bladder cancer, urothelial cell carcinoma;        renal carcinomas including renal cell carcinoma, metastatic        renal cell carcinoma, metastatic renal clear cell carcinoma;        gastro-intestinal cancers including colorectal cancer,        metastatic colorectal cancer, familial adenomatous polyposis        (FAP), oesophageal cancer, gastric cancer, gallbladder cancer,        cholangiocarcinoma, hepatocellular carcinoma, and pancreatic        cancer such as pancreatic adenocarcinoma or pancreatic ductal        carcinoma; endometrial cancer; ovarian cancer; cervical cancer;        neuroblastoma; prostate cancer including castrate-resistant        prostate cancer; brain tumors including brain metastases,        malignant gliomas, glioblastoma multiforme, medulloblastoma,        meningiomas; breast cancer including triple negative breast        carcinoma; oral tumors; nasopharyngeal tumors; thoracic cancer;        head and neck cancer; leukemias including acute myeloid        leukemia, adult T-cell leukemia; carcinomas; adenocarcinomas;        thyroid carcinoma including papillary thyroid carcinoma;        choriocarcinoma; Ewing's sarcoma; osteosarcoma;        rhabdomyosarcoma; Kaposi's sarcoma; lymphoma including Burkitt's        lymphoma, Hodgkin's lymphoma, MALT lymphoma; multiple myelomas;        and virally induced tumors; especially melanoma; lung cancer;        bladder cancer; renal carcinomas; gastro-intestinal cancers;        endometrial cancer; ovarian cancer; cervical cancer; and        neuroblastoma);        as well as further diseases or disorders relating to the EP2        and/or EP4 receptors such as:    -   pain (notably inflammatory pain and painful menstruation);    -   endometriosis;    -   autosomal dominant polycystic kidney disease;    -   acute ischemic syndromes in atherosclerotic patients;    -   pneumonia; and    -   neurodegenerative diseases including amyotrophic lateral        sclerosis, stroke; Parkinson disease, Alzheimer's disease and        HIV associated dementia;    -   and EP2 and/or EP4 antagonists may further be used to control        female fertility.

The compounds of formulae (I), (II), or (III) according to any one ofembodiments 1) to 29) are in particular useful as therapeutic agents forthe prevention/prophylaxis or treatment of a cancer. They can be used assingle therapeutic agents or in combination with one or morechemotherapy agents and/or radiotherapy and/or targeted therapy. Suchcombined treatment may be effected simultaneously, separately, or over aperiod of time.

The invention, thus, also relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier material, and:

-   -   a compound of formulae (I), (II), or (III) according to any one        of embodiments 1) to 29);    -   and one or more cytotoxic chemotherapy agents.

The invention, thus, further relates to a kit comprising

-   -   a pharmaceutical composition, said composition comprising a        pharmaceutically acceptable carrier material, and:        -   a compound of formulae (I), (II), or (Ill) according to any            one of embodiments 1) to 29);    -   and instructions how to use said pharmaceutical composition for        the prevention/prophylaxis or the treatment of a cancer, in        combination with chemotherapy and/or radiotherapy and/or        targeted therapy.

The terms “radiotherapy” or “radiation therapy” or “radiation oncology”,refer to the medical use of ionizing radiation in theprevention/prophylaxis (adjuvant therapy) and/or treatment of cancer;including external and internal radiotherapy.

The term “targeted therapy” refers to the prevention/prophylaxis(adjuvant therapy) and/or treatment of cancer with one or moreanti-neoplastic agents such as small molecules or antibodies which acton specific types of cancer cells or stromal cells. Some targetedtherapies block the action of certain enzymes, proteins, or othermolecules involved in the growth and spread of cancer cells. Other typesof targeted therapies help the immune system kill cancer cells(immunotherapies); or inhibit angiogenesis, the growth and formation ofnew blood vessels in the tumor; or deliver toxic substances directly tocancer cells and kill them. An example of a targeted therapy which is inparticular suitable to be combined with the compounds of the presentinvention is immunotherapy, especially immunotherapy targeting theprogrammed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1(Zelenay et al., 2015, Cell 162, 1-14; Yongkui Li et al., Oncoimmunology2016, 5(2):e1074374).

When used in combination with the compounds of formulae (I), (II), or(III), the term “targeted therapy” especially refers to agents such as:

-   -   a) Epidermal growth factor receptor (EGFR) inhibitors or        blocking antibodies (for example Gefitinib, Erlotinib, Afatinib,        Icotinib, Lapatinib, Panitumumab, Zalutumumab, Nimotuzumab,        Matuzumab and Cetuximab);    -   b) RAS/RAF/MEK pathway inhibitors (for example Vemurafenib,        Sorafenib, Dabrafenib, GDC-0879, PLX-4720, LGX818, RG7304,        Trametinib (GSK1120212), Cobimetinib (GDC-0973/XL518),        Binimetinib (MEK162, ARRY-162), Selumetinib (AZD6244));    -   c) Aromatase inhibitors (for example Exemestane, Letrozole,        Anastrozole, Vorozole, Formestane, Fadrozole);    -   d) Angiogenesis inhibitors, especially VEGF signalling        inhibitors such as Bevacuzimab (Avastin), Ramucirumab, Sorafenib        or Axitinib;    -   e) Immune Checkpoint inhibitors (for example: anti-PD1        antibodies such as Pembrolizumab (Lambrolizumab, MK-3475),        Nivolumab, Pidilizumab (CT-011), AMP-514/MED10680, PDR001,        SHR-1210; REGN2810, BGBA317; fusion proteins targeting PD-1 such        as AMP-224; small molecule anti-PD1 agents such as for example        compounds disclosed in WO2015/033299, WO2015/044900 and        WO2015/034820; anti-PD1L antibodies, such as BMS-936559,        atezolizumab (MPDL3280A, RG7446), MED14736, avelumab        (MSB0010718C), durvalumab (MED14736); anti-PDL2 antibodies, such        as AMP224; anti-CTLA-4 antibodies, such as ipilimumab,        tremilmumab; anti-Lymphocyte-activation gene 3 (LAG-3)        antibodies, such as BMS-986016, IMP701, MK-4280, ImmuFact        IMP321; anti T cell immunoglobulin mucin-3 (TIM-3) antibodies,        such as MBG453; anti-CD137/4-1BB antibodies, such as        BMS-663513/urelumab, PF-05082566; anti T cell immunoreceptor        with Ig and ITIM domains (TIGIT) antibodies, such as RG6058        (anti-TIGIT, MTIG7192A);    -   f) Vaccination approaches (for example dendritic cell        vaccination, peptide or protein vaccination (for example with        gp100 peptide or MAGE-A3 peptide);    -   g) Re-introduction of patient derived or allogenic (non-self)        cancer cells genetically modified to secrete immunomodulatory        factors such as granulocyte monocyte colony stimulating factor        (GMCSF) gene-transfected tumor cell vaccine (GVAX) or        Fms-related tyrosine kinase 3 (Flt-3) ligand gene-transfected        tumor cell vaccine (FVAX),or Toll like receptor enhanced GM-CSF        tumor based vaccine (TEGVAX);    -   h) T-cell based adoptive immunotherapies, including chimeric        antigen receptor (CAR) engineered T-cells (for example CTL019);    -   i) Cytokine or immunocytokine based therapy (for example        Interferon alpha, interferon beta, interferon gamma, interleukin        2, interleukin 15);    -   j) Toll-like receptor (TLR) agonists (for example resiquimod,        imiquimod, glucopyranosyl lipid A, CpG oligodesoxynucleotides);    -   k) Thalidomide analogues (for example Lenalidomide,        Pomalidomide);    -   l) Indoleamin-2,3-Dioxgenase (IDO) and/or        Tryptophane-2,3-Dioxygenase (TDO) inhibitors (for example        RG6078/NLG919/GDC-0919; Indoximod/1MT (1-methyltryptophan),        INCB024360/Epacadostat, PF-06840003 (EOS200271), F001287);    -   m) Activators of T-cell co-stimulatory receptors (for example        anti-OX40/CD134 (Tumor necrosis factor receptor superfamily,        member 4, such as RG7888 (MOXR0916), 9B12; MED16469, GSK3174998,        MED10562), anti OX40-Ligand/CD252; anti-glucocorticoid-induced        TNFR family related gene (GITR) (such as TRX518, MED11873,        MK-4166, BMS-986156), anti-CD40 (TNF receptor superfamily        member 5) antibodies (such as Dacetuzumab (SGN-40), HCD122,        CP-870,893, RG7876, ADC-1013, APX005M, SEA-CD40);        anti-CD40-Ligand antibodies (such as BG9588); anti-CD27        antibodies such as Varlilumab);    -   n) Molecules binding a tumor specific antigen as well as a        T-cell surface marker such as bispecific antibodies (for example        RG7802 targeting CEA and CD3) or antibody fragments, antibody        mimetic proteins such as designed ankyrin repeat proteins        (DARPINS), bispecific T-cell engager (BITE, for example AMG103,        AMG330);    -   o) Antibodies or small molecular weight inhibitors targeting        colony-stimulating factor-1 receptor (CSF-1R) (for example        Emactuzumab (RG7155), Cabiralizumab (FPA-008), PLX3397);    -   p) Agents targeting immune cell check points on natural killer        cells such as antibodies against Killer-cell immunoglobulin-like        receptors (KIR) for example Lirilumab (IPH2102/BMS-986015);    -   q) Agents targeting the Adenosine receptors or the ectonucleases        CD39 and CD73 that convert ATP to Adenosine, such as MED19447        (anti-CD73 antibody), PBF-509; CPI-444 (Adenosine A2a receptor        antagonist).

When used in combination with the compounds of formulae (I), (II), or(III), immune checkpoint inhibitors such as those listed under d), andespecially those targeting the programmed cell death receptor 1 (PD-1receptor) or its ligand PD-L1, are preferred.

The term “chemotherapy” refers to the treatment of cancer with one ormore cytotoxic anti-neoplastic agents (“cytotoxic chemotherapy agents”).Chemotherapy is often used in conjunction with other cancer treatments,such as radiation therapy or surgery. The term especially refers toconventional cytotoxic chemotherapeutic agents which act by killingcells that divide rapidly, one of the main properties of most cancercells. Chemotherapy may use one drug at a time (single-agentchemotherapy) or several drugs at once (combination chemotherapy orpolychemotherapy). Chemotherapy using drugs that convert to cytotoxicactivity only upon light exposure is called photochemotherapy orphotodynamic therapy.

The term “cytotoxic chemotherapy agent” or “chemotherapy agent” as usedherein refers to an active anti-neoplastic agent inducing apoptosis ornecrotic cell death. When used in combination with the compounds offormulae (I), (II), or (III), the term especially refers to conventionalcytotoxic chemotherapy agents such as:

-   a) alkylating agents (for example mechlorethamine, chlorambucil,    cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine,    melphalan, dacarbazine, temozolomide, fotemustine, thiotepa or    altretamine; especially cyclophosphamide, carmustine, melphalan,    dacarbazine, or temozolomide);-   b) platinum drugs (especially cisplatin, carboplatin or    oxaliplatin);-   c) antimetabolite drugs (for example 5-fluorouracil, folic    acid/leucovorin, capecitabine, 6-mercaptopurine, methotrexate,    gemcitabine, cytarabine, fludarabine or pemetrexed; especially    5-fluorouracil, folic acid/leucovorin, capecitabine, methotrexate,    gemcitabine or pemetrexed);-   d) anti-tumor antibiotics (for example daunorubicin, doxorubicin,    epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C or    mitoxantrone; especially doxorubicin);-   e) mitotic inhibitors (for example paclitaxel, docetaxel,    ixabepilone, vinblastine, vincristine, vinorelbine, vindesine or    estramustine; especially paclitaxel, docetaxel, ixabepilone or,    vincristine); or-   f) topoisomerase inhibitors (for example etoposide, teniposide,    topotecan, irinotecan, diflomotecan or elomotecan; especially    etoposide or irinotecan).

When used in combination with the compounds of formulae (I), (II), or(Ill), preferred cytotoxic chemotherapy agents are the above-mentionedalkylating agents (notably fotemustine, cyclophosphamide, ifosfamide,carmustine, dacarbazine and prodrugs thereof such as especiallytemozolomide or pharmaceutically acceptable salts of these compounds; inparticular temozolomide); mitotic inhibitors (notably paclitaxel,docetaxel, ixabepilone; or pharmaceutically acceptable salts of thesecompounds; in particular paclitaxel); platinum drugs (notably cisplatin,oxaliplatin and carboplatin); as well etoposide and gemcitabine.

Chemotherapy may be given with a curative intent or it may aim toprolong life or to palliate symptoms.

-   -   Combined modality chemotherapy is the use of drugs with other        cancer treatments, such as radiation therapy or surgery.    -   Induction chemotherapy is the first line treatment of cancer        with a chemotherapeutic drug. This type of chemotherapy is used        for curative intent.    -   Consolidation chemotherapy is the given after remission in order        to prolong the overall disease free time and improve overall        survival. The drug that is administered is the same as the drug        that achieved remission.    -   Intensification chemotherapy is identical to consolidation        chemotherapy but a different drug than the induction        chemotherapy is used.    -   Combination chemotherapy involves treating a patient with a        number of different drugs simultaneously. The drugs differ in        their mechanism and side effects. The biggest advantage is        minimising the chances of resistance developing to any one        agent. Also, the drugs can often be used at lower doses,        reducing toxicity.    -   Neoadjuvant chemotherapy is given prior to a local treatment        such as surgery, and is designed to shrink the primary tumor. It        is also given to cancers with a high risk of micrometastatic        disease.    -   Adjuvant chemotherapy is given after a local treatment        (radiotherapy or surgery). It can be used when there is little        evidence of cancer present, but there is risk of recurrence. It        is also useful in killing any cancerous cells that have spread        to other parts of the body. These micrometastases can be treated        with adjuvant chemotherapy and can reduce relapse rates caused        by these disseminated cells.    -   Maintenance chemotherapy is a repeated low-dose treatment to        prolong remission.    -   Salvage chemotherapy or palliative chemotherapy is given without        curative intent, but simply to decrease tumor load and increase        life expectancy. For these regimens, a better toxicity profile        is generally expected.

“Simultaneously”, when referring to an administration type, means in thepresent application that the administration type concerned consists inthe administration of two or more active ingredients and/or treatmentsat approximately the same time; wherein it is understood that asimultaneous administration will lead to exposure of the subject to thetwo or more active ingredients and/or treatments at the same time. Whenadministered simultaneously, said two or more active ingredients may beadministered in a fixed dose combination, or in an equivalent non-fixeddose combination (e.g. by using two or more different pharmaceuticalcompositions to be administered by the same route of administration atapproximately the same time), or by a non-fixed dose combination usingtwo or more different routes of administration; wherein saidadministration leads to essentially simultaneous exposure of the subjectto the two or more active ingredients and/or treatments. For example,when used in combination with chemotherapy and/or suitable targetedtherapy, the present EP2/EP4 antagonists would possibly be used“simultaneously”.

“Fixed dose combination”, when referring to an administration type,means in the present application that the administration type concernedconsists in the administration of one single pharmaceutical compositioncomprising the two or more active ingredients.

“Separately”, when referring to an administration type, means in thepresent application that the administration type concerned consists inthe administration of two or more active ingredients and/or treatmentsat different points in time; wherein it is understood that a separateadministration will lead to a treatment phase (e.g. at least 1 hour,notably at least 6 hours, especially at least 12 hours) where thesubject is exposed to the two or more active ingredients and/ortreatments at the same time; but a separate administration may also leadto a treatment phase where for a certain period of time (e.g. at least12 hours, especially at least one day) the subject is exposed to onlyone of the two or more active ingredients and/or treatments. Separateadministration especially refers to situations wherein at least one ofthe active ingredients and/or treatments is given with a periodicitysubstantially different from daily (such as once or twice daily)administration (e.g. wherein one active ingredient and/or treatment isgiven e.g. once or twice a day, and another is given e.g. every otherday, or once a week or at even longer distances). For example, when usedin combination with radiotherapy, the present EP2/EP4 antagonists wouldpossibly be used “separately”.

By administration “over a period of time” is meant in the presentapplication the subsequent administration of two or more activeingredients and/or treatments at different times. The term in particularrefers to an administration method according to which the entireadministration of one of the active ingredients and/or treatments iscompleted before the administration of the other/the others begins. Inthis way it is possible to administer one of the active ingredientsand/or treatments for several months before administering the otheractive ingredient(s) and/or treatment(s).

Administration “over a period of time” also encompasses situationswherein the compound of formulae (I), (II), or (III) would be used in atreatment that starts after termination of an initial chemotherapeutic(for example an induction chemotherapy) and/or radiotherapeutictreatment and/or targeted therapy treatment, wherein optionally saidtreatment would be in combination with a further/an ongoingchemotherapeutic and/or radiotherapeutic treatment and/or targetedtherapy treatment (for example in combination with a consolidationchemotherapy, an intensification chemotherapy, an adjuvant chemotherapy,or a maintenance chemotherapy; or radiotherapeutic equivalents thereof);wherein such further/ongoing chemotherapeutic and/or radiotherapeutictreatment and/or targeted therapy treatment would be simultaneously,separately, or over a period of time in the sense of “not given with thesame periodicity”.

The compounds of formulae (I), (II), or (III) as defined inembodiments 1) to 29) are also useful in a method of modulating animmune response in a subject having a tumor, comprising theadministration of an effective amount of the compound of formulae (I),(II), or (III) [wherein notably said administration of said effectiveamount results in the pharmacologically active blockage of the EP2receptors, or of the EP4 receptors, or of both the EP2 and the EP4receptors]; wherein said effective amount reactivates the immune systemin the tumor of said subject; wherein especially said effective amount:

-   -   counteracts the polarization of tumor-associated macrophages        towards tumor-promoting M2 macrophages; and/or    -   down-regulates the activation, expansion and/or the effector        function of immunosuppressive cells that have accumulated in a        tumor (especially of regulatory T cells (Tregs) and/or myeloid        derived suppressor cells (MDSC)); and/or    -   up-regulates IFN-γ and/or TNF-α and/or IL-12 and/or IL-2        expression in immune cells such as natural killer cells,        T-cells, dendritic cells and macrophages (leading to the        induction of tumor cell apoptosis and/or restrained        tumorigenesis); and/or    -   directly or indirectly counteracts the suppressed activation,        IL-2 responsiveness and expansion of cytotoxic T-cells (thereby        decreasing local immunsuppresion).

The compounds of formulae (I), (II), or (III) as defined inembodiments 1) to 29) are also useful in a method of diminishing tumorgrowth and/or reducing tumor size in a subject having a tumor,comprising the administration of an effective amount of the compound offormulae (I), (II), or (III) [wherein notably said administration ofsaid effective amount results in the pharmacologically active blockageof the EP2 receptors, or of the EP4 receptors, or of both the EP2 andthe EP4 receptors]; wherein said effective amount down-regulates tumorangiogenesis (especially by decreasing endothelial cell motility and/orsurvival, and/or by decreasing the expression of VEGF (vascularendothelial growth factor)); and/or wherein said effective amountdiminishes tumor cell survival and/or induces tumor cell apoptosis(especially via inhibition of PI3K/AKT and MAPK signalling).

The compounds of formulae (I), (II), or (III) as defined inembodiments 1) to 29) are also useful in a method of modulating animmune response in a subject having a tumor, comprising theadministration of an effective amount of the compound of formulae (I),(II), or (III) [wherein notably said administration of said effectiveamount results in the pharmacologically active blockage of the EP2receptors, or of the EP4 receptors, or of both the EP2 and the EP4receptors]; wherein said effective amount reactivates the immune systemin the tumor of said subject; wherein said effective amount activatesthe cytotoxicity and cytokine production of natural killer cells and/orcytotoxic T-cells.

Besides, any preferences and (sub-)embodiments indicated for thecompounds of formulae (II) or (III) (whether for the compoundsthemselves, salts thereof, compositions containing the compounds orsalts thereof, or uses of the compounds or salts thereof, etc.) applymutatis mutandis to compounds of formula (I).

Preparation of Compounds of Formulae (I), (II), or (III):

The compounds of formulae (I), (II), or (Ill) can be prepared bywell-known literature methods, by the methods given below, by themethods given in the experimental part below or by analogous methods.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by a person skilledin the art by routine optimisation procedures. In some cases the orderof carrying out the following reaction schemes, and/or reaction steps,may be varied to facilitate the reaction or to avoid unwanted reactionproducts. In the general sequence of reactions outlined below, thegeneric groups R¹, R³, R^(4a), R^(4b), R^(5a), R^(5b) and Ar¹ are asdefined for formulae (I), (II), or (III). Other abbreviations usedherein are explicitly defined, or are as defined in the experimentalsection. In some instances the generic groups R¹, R³, R^(4a), R^(4b),R^(5a), R^(5b) and Ar¹ might be incompatible with the assemblyillustrated in the schemes below and so will require the use ofprotecting groups (PG). The use of protecting groups is well known inthe art (see for example “Protective Groups in Organic Synthesis”, T. W.Greene, P. G. M. Wuts, Wiley-Interscience, 1999). For the purposes ofthis discussion, it will be assumed that such protecting groups asnecessary are in place. In some cases the final product may be furthermodified, for example, by manipulation of substituents to give a newfinal product. These manipulations may include, but are not limited to,reduction, oxidation, alkylation, acylation, hydrolysis andtransition-metal catalysed cross-coupling reactions which are commonlyknown to those skilled in the art. The compounds obtained may also beconverted into salts, especially pharmaceutically acceptable salts, in amanner known per se.

Compounds of formulae (I), (II), or (III) of the present invention canbe prepared according to the general sequence of reactions outlinedbelow.

A general synthetic route allowing the preparation of compounds offormula (I) is presented in scheme 1. Thus, precursors (3) can beobtained by nucleophilic aromatic substitutions between primary amines(1) and pyrimidines (2) (wherein X is a chlorine, a bromine or aniodine), in the presence of a base such as TEA, DIPEA or K₂CO₃, in asolvent such as isopropanol, butanol, DMF or THF, at RT or at elevatedtemperatures. Compounds of formula (I) can be produced viametal-catalyzed cross-coupling reactions of the pyrimidine halidederivatives (3) with a compound of formula (4), for example Suzukicouplings when compounds (4) are boronic acids or boronic esters.Typical Suzuki cross-coupling reactions may be carried out in thepresence of a base such as K₂CO₃, Cs₂CO₃, Na₂CO₃, K₃PO₄, or CsF and acatalyst such as Pd(PPh₃)₄, Pd(dppf)C₂ or Pd(OAc)₂, in a solvent likeethanol, THF, water, or RMs thereof, typically at elevated temperatures.Boronic acids or boronate esters A4 can be obtained from commercialsources, or synthesized by methods described in the literature, or bymethods known by a person skilled in the art. A boronic acid derivativecan be formed by the Miyaura borylation reaction, by cross-coupling ofbis(pinacolato)diboron with aryl halides or triflates, in the presenceof a base such as potassium acetate and a catalyst such as Pd(dppf)Cl₂.Alternatively, a boronic acid derivative can be formed by alithiation/borylation sequence, typically at low temperatures, usingbutyllithium or lithium diisopropylamide as the base, andtri-isopropylborate or isopropoxyboronic acid pinacol ester, in asolvent such as diethyl ether or THF. In a variant, compounds of formula(I) can be prepared via nucleophilic aromatic substitutions betweenprimary amines (1) and substituted pyrimidine halides (5), wherein X isa chlorine, a bromine or an iodine. Alternatively, compounds of formula(I) can be synthesized by reacting a compound of formula (1) with acompound of formula (5) wherein X represents OH, in presence of acbopoupling agent such as BOP, PyBOP or hexachlorocyclotriphosphazene,in presence of a base such as DBU, DIPEA or TEA in a solvent such asTHF, MeCN or DMF, at low temperatures, or at RT or at elevatedtemperatures.

Preparations of the required primary amines 1 are described in scheme 2.Aminoethylated (hetero)aromatics (8) can be produced via Suzuki-Miyauracross-coupling reactions of the corresponding (hetero)aromaticelectrophiles (6) (bromides, iodides or triflates) with Boc-protectedpotassium 3-aminoethyltrifluoroborates (7). Such cross-couplingreactions can be performed using described conditions [Pd(dppf)C₂ orcombination of Pd(OAc)₂ and RuPhos as the catalytic system, Cs₂CO₃ as abase, in a RM of toluene/H₂O, at elevated temperatures]. Thecorresponding primary amines (1) can be obtained after Boc-deprotectionof derivatives (8), under acidic conditions, and can be converted intocompounds of formula (I) with the synthetic sequences described inscheme 1. In a variant presented in scheme 2, primary amines (1) can beprepared starting from carbonyl precursors (9) and nitro compounds (10)via Henry reaction (butylamine/acetic acid/molecular sieves/90° C.) andsubsequent reduction of the produced nitroalkenes (11) (lithium aluminumhydride/THF, or NaBH₄/BF₃.Et₂O/THF).

The pyrimidines of formula (5) can be obtained by metal-catalyzedcross-coupling reactions between compounds of formula (4), typicallyboronic acids or esters, and di-halo-pyrimidines of formula (2), whereinX═Cl, Br or I (Scheme 3). Compounds of formula (5) wherein X═OH can beobtained by de-alkylation of compounds of formula (13), wherein Alk istypically Me or Et. In turn, (13) can be formed by a cross-couplingreaction between compounds of formula (12), wherein X═Cl, Br, I, andcompounds of formula (4), typically boronic acids or esters.

The following examples are provided to illustrate the invention. Theseexamples are illustrative only and should not be construed as limitingthe invention in any way.

Experimental Part

I. Chemistry

All temperatures are stated in ° C. Commercially available startingmaterials were used as received without further purification. Unlessotherwise specified, all reactions were carried out in oven-driedglassware under an atmosphere of nitrogen. Compounds were purified byflash column chromatography on silica gel or by preparative HPLC.Compounds described in the invention are characterised by LC-MS data(retention time t_(R) is given in min; molecular weight obtained fromthe mass spectrum is given in g/mol) using the conditions listed below.In cases where compounds of the present invention appear as a RM ofconformational isomers, particularly visible in their LC-MS spectra, theretention time of the most abundant conformer is given. In some casescompounds are isolated after purification in form of the correspondingammonium salt (*1), such compounds are marked accordingly.

Analytical LC-MS Equipment:

HPLC pump: Binary gradient pump, Agilent G4220A or equivalent

Autosampler: Gilson LH215 (with Gilson 845z injector) or equivalent

Column compartment: Dionex TCC-3000RS or equivalent

Degasser: Dionex SRD-3200 or equivalent

Make-up pump: Dionex HPG-3200SD or equivalent

DAD detector: Agilent G4212A or equivalent

MS detector: Single quadrupole mass analyzer, Thermo Finnigan MSQPlus orequivalent

ELS detector: Sedere SEDEX 90 or equivalent

LC-MS with Acidic Conditions

Method A:

Column: Zorbax SB-aq (3.5 μm, 4.6×50 mm). Conditions: MeCN [eluent A];water+0.04% TFA [eluent B]. Gradient: 95% B→5% B over 1.5 min (flow: 4.5mL/min). Detection: UVNis+MS.

Method B:

Column: Zorbax RRHD SB-aq (1.8 μm, 2.1×50 mm). Conditions: MeCN [eluentA]; water+0.04% TFA [eluent B]. Gradient: 95% B→5% B over 2.0 min (flow:0.8 mL/min). Detection: UVNis+MS.

Method C:

Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector, DAD:Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Column ACQUITY UPLCCSH C18 1.7 um 2.1×50 mm from Waters, thermostated in the Acquity UPLCColumn Manager at 60° C. Eluents: A: H2O+0.05% formic acid; B:MeCN+0.045% formic acid. Method: Gradient: 2% B 98% B over 2.0 min.Flow: 1.0 mL/min. Detection: UV 214 nm and ELSD, and MS, t_(R) is givenin min.

LC-MS with Basic Conditions

Method D:

Column: Waters BEH C₁₈, 3.0×50 mm, 2.5 μm, Eluents: A: Water/NH3[c(NH₃)=13 mmol/I], B: MeCN, Method: 5% B to 95% B in 1.2 min, Flow 1.6ml/min, Detection UV: 214 nm

Preparative HPLC Equipment:

Gilson 333/334 HPLC pump equipped with Gilson LH215, Dionex SRD-3200degasser,

Dionex ISO-3100A make-up pump, Dionex DAD-3000 DAD detector, Singlequadrupole mass analyzer MS detector, Thermo Finnigan MSQ Plus,MRA100-000 flow splitter, Polymer Laboratories PL-ELS1000 ELS detector

Preparative HPLC with Basic Conditions

Column: Waters XBridge (10 μm, 75×30 mm). Conditions: MeCN [eluent A];water+0.5% NH₄OH (25% aq.) [eluent B]; Gradient see Table 1 (flow: 75mL/min), the starting percentage of Eluent A (x) is determined dependingon the polarity of the compound to purify. Detection: UVNis+MS

TABLE 1 t (min) 0 0.01 4.0 6.0 6.2 6.6 Eluent A (%) x x 95 95 x x EluentB (%) 100-x 100-x 5 5 100-x 100-x

Preparative HPLC with Acidic Conditions

Column: Waters Atlantis T3 (10 μm, 75×30 mm). Conditions: MeCN [eluentA]; water+0.5% HCO₂H [eluent B]; Gradient see Table 2 (flow: 75 mL/min),the starting percentage of Eluent A (x) is determined depending on thepolarity of the compound to purify. Detection: UVNis+MS

TABLE 2 t (min) 0 0.01 4.0 6.0 6.2 6.6 Eluent A (%) x x 95 95 x x EluentB (%) 100-x 100-x 5 5 100-x 100-x

Abbreviations (as Used Hereinbefore or Hereinafter):

-   aq. aqueous-   atm atmosphere-   Boc tert-butoxycarbonyl-   BOP (benzotriazol-1-yloxy)-tris(dimethylamino)-phosphonium    hexafluorophosphate-   d days-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCM dichloromethane-   DIPEA diisopropyl-ethylamine, Hünig's base-   DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   dppf 1,1′-bis(diphenylphosphino)ferrocene-   Et ethyl-   Et₂O diethylether-   EtOAc ethyl acetate-   EtOH ethanol-   Ex. example-   FC flash chromatography on silica gel-   h hour(s)-   hept heptane(s)-   HPLC high performance liquid chromatography-   HV high vacuum conditions-   ^(i)Bu isobutyl-   ^(i)Pr isopropyl-   LAH lithium aluminium hydride-   LC-MS liquid chromatography-mass spectrometry-   Lit. Literature-   Me methyl-   MeCN acetonitrile-   MeOH methanol-   mL milliliter-   min minute(s)-   MW microwave-   NaHMDS sodium bis(trimethylsilyl)amide-   ^(n)Pr n-propyl-   OAc acetate-   Pd₂dba₃ Tris(dibenzylideneacetone)dipalladium(0)-   Pd(dppf)Cl₂.DCM    [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II)    complex with dichloromethane-   Ph phenyl-   PPh₃ triphenyl phosphine-   prep. preparative-   PyBOP (benzotriazol-1-yl-oxy)-tripyrrolidino-phosphonium    hexafluorophosphate-   rac racemic-   RM reaction mixture-   RT room temperature-   RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl-   s second(s)-   sat. saturated-   tBu tert-butyl=tertiary butyl-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   tosyl p-toluene-sulfonyl-   t_(R) retention time-   triflate trifluoromethanesulfonate

General Procedures

General Procedure A: Nitro-Aldol Condensation and Dehydration

To a solution of aromatic aldehyde (10 mmol) in nitromethane (20 mL) atRT are added butylamine (0.117 mL, 1.18 mmol), acetic acid (0.116 mL,2.04 mmol) and 4 Å molecular sieves (100 mg). The RM is stirred at 90°C. for 1 h, then cooled to RT and concentrated in vacuo. The residue ispartitioned between EtOAc and water. The organic phase is washed oncemore with water then with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The crude product is purified by preparative HPLCor by FC if needed.

General Procedure B: Nitrostyrene Reduction

LAH (2M in THF, 11 mL, 21.8 mmol) is added dropwise at 0° C. to asolution of nitrostyrene (6.24 mmol) in THF (30 mL). The RM is stirredat RT for 2 h, then cooled to 0° C., and quenched carefully with water(1.28 mL), 15% aqueous NaOH (1.28 mL), and water (3.9 mL). The resultingsuspension is stirred at RT for 1 h, then filtered and washed with Et₂O.The filtrate is concentrated under reduced pressure, and the crudeproduct is purified by preparative HPLC or by FC if needed.

Alternatively, to a solution of sodium borohydride (251 mg, 6.51 mmol)in THF (7 mL) at 0° C. is added BF₃.Et₂O (1.06 mL, 8.14 mmol). The RM isstirred 10 min at 0° C. then 15 min at RT. A solution of nitrostyrene(1.36 mmol) in THF (3 mL) is added dropwise and the RM is refluxedovernight. The RM is cooled at 0° C. and treated carefully with 2N HCl(8.8 mL, 17.6 mmol). The RM is heated for 1 h at 80° C., then cooled toRT, and the organic solvent is removed under reduced pressure. Theremaining aqueous layer is extracted with Et₂O. The aqueous layer istreated with 10% NaOH to reach pH >12 and extracted 3 times with EtOAc.The combined organic layers are washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude product is purified by preparative HPLCor by FC if needed.

General Procedure C: Suzuki Miyaura Coupling with Trifluoroborates

A reaction vessel is charged with the aryl-bromide or triflate (1.91mmol), potassium tert-butyl n-[2-(trifluoroboranuidyl)ethyl]carbamate(555 mg, 2.1 mmol), cesium carbonate (2489 mg, 7.64 mmol), palladium(II)acetate (21.5 mg, 0.0955 mmol), RuPhos (93.8 mg, 0.191 mmol) and toluene(15 mL) and water (5 mL). The RM is flushed with argon, then heated at95° C. overnight. The RM is cooled to RT and filtered through a glassmicrofiber. The filtrate is concentrated under reduced pressure. Theresidue is partitioned between DCM and NH₄Cl saturated solution. Phasesare separated and the aqueous layer is extracted twice more with DCM.The combined organic layers are then washed with brine, dried overMgSO₄, filtered and evaporated in vacuo. The crude product is purifiedby preparative HPLC or by FC if needed.

General Procedure D: Boc Deprotection (TFA)

To a solution of Boc-protected amine (1.91 mmol) in DCM (40 mL) at 0° C.is added TFA (10 mL). The RM is stirred for 2 h, letting the temperaturerise to RT. It is then concentrated in vacuo. The residue is dissolvedagain in DCM and evaporated in vacuo (twice), affording the free amineas TFA salt.

General Procedure E: Boc Deprotection (HCl)

A solution of Boc-protected amine (1.91 mmol) in DCM (40 mL) at 0° C. isadded HCl (4N in dioxane, 10 mL). The RM is stirred for 2 h, letting thetemperature rise to RT. It is then concentrated in vacuo, affording thefree amine as HCl salt.

General Procedure F: SNAr of 4,6-di-halo-pyrimidine

A solution of aryl-ethylamine (21.1 mmol), 4,6-dichloropyrimidine (3.00g, 20.1 mmol) and TEA (3.08 mL, 22.2 mmol) in 2-propanol (50 mL) isrefluxed for 2 h, then allowed to cool to RT and concentrated underreduced pressure. The residue is partitioned between sat. aq. NaHCO₃solution and EtOAc. The layers are separated and the aqueous layer isextracted once more with EtOAc. The combined organic layers are washedwith water, brine, dried over MgSO₄, filtered and the solvent is removedin vacuo. The crude product is purified by preparative HPLC or by FC ifneeded.

General Procedure G: Suzuki Coupling with Pd(PPh₃)₄

A RM of the respective pyrimidine halide derivative (3) (0.15 mmol), therespective boronic acid derivative (4) (0.18 mmol), and K₂CO₃ 2M (0.3mL, 0.6 mmol) in ethanol (3 mL) is purged with argon, Pd(PPh₃)₄(0.0075mmol) is added, and the RM is heated at 90° C. overnight. Alternatively,the reaction can be performed in a MW apparatus, at 120° C. for 15-30min. The RM is filtered through a 0.45 um Glass MicroFiber filter,washed with EtOH/MeCN and DMF. The filtrate is purified either bypreparative HPLC or FC. Alternatively, it is diluted with water, ifneeded the pH is adjusted, and extracted with EtOAc (3×). The combinedorganic extracts are dried (MgSO₄) and concentrated under reducedpressure. The residue is purified by preparative HPLC or by FC.

General Procedure H: Suzuki Coupling with Pd(PPh₃)₄ Followed by EsterHydrolysis

A RM of the respective pyrimidine halide derivative (3) (0.15 mmol), therespective boronic acid derivative (4) (0.18 mmol), and K₂CO₃ 2M (0.3mL, 0.6 mmol) in EtOH (3 mL) is purged with argon, Pd(PPh₃)₄(0.0075mmol) is added, and the RM is heated at 90° C. overnight. Alternatively,the reaction can be performed in a MW apparatus, at 120° C. for 15-30min. NaOH (32% solution, 0.5 mL) is added, and the RM is stirred at RTfor 2-20 h or at 90° C. for 0.5-20 h. It is then filtered through a 0.45um Glass MicroFiber filter, washed with EtOH and water. The filtrate iseither purified directly by preparative HPLC or diluted with 1N HCl, andextracted 3× with EtOAc. The combined organic extracts are dried (MgSO₄)and concentrated under reduced pressure. The residue is purified bypreparative HPLC or by FC if needed.

General Procedure I: Phosphonium-Mediated SNAr

To a solution of 6-hydroxy-pyrimidine derivative (0.196 mmol) in DMF (2mL) and Et₃N (0.109 mL, 0.784 mmol) is added PyBOP (163 mg, 0.313 mmol).The yellow solution is stirred at RT for 15 min, then the respectivearyl-ethylamine (0.245 mmol) is added and the RM is stirred at 80° C.overnight. The RM is cooled to RT and treated with a few drops of waterand purified by preparative HPLC. Alternatively, the RM is diluted withAcOEt and washed twice with brine. The organic layer is dried overMgSO₄, filtered and concentrated. The residue is purified by preparativeHPLC or by FC if needed.

Alternatively, a solution of 6-hydroxy-pyrimidine derivative (0.1 mmol)in DMF (1 mL) is treated with DBU (0.15 mmol) and BOP (0.13 mmol). Thesolution is stirred at RT for 15 min-1 h, then the respectivearyl-ethylamine (0.125 mmol) is added, and the RM is stirred at 80° C.for 2-20 h. The RM is cooled to RT and treated with a few drops of waterand purified by preparative HPLC. Or the RM is diluted with EtOAc andwashed twice with brine. The organic layer is dried over MgSO₄, filteredand concentrated. The residue is purified by preparative HPLC or by FCif needed.

A—PREPARATION OF PRECURSORS AND INTERMEDIATES A.1. Synthesis ofPyrimidine Halide Derivatives of Formula (3) A.1.1.6-Chloro-N-(2-(naphthalen-1-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(1-naphtyl) ethylamine hydrochloride and4,6-dichloropyrimidine, and obtained as a yellow solid. LC-MS A:t_(R)=0.91 min; [M+H]⁺=283.94.

Following the procedure described for the synthesis of A.1.1. describedabove, the following pyrimidine-halide derivatives of formula (3) aresynthesized, starting from the corresponding commercially available arylethylamines and 4,6-dichloropyrimidine or 4,6-diiodopyrimidine (seetable 3).

TABLE 3 Pyrimidine halide derivatives A.1.2.-A.1-24. MS Data t_(R) [min]m/z No. Compound (LC-MS) [M + H]⁺ A.1.2.1-N-(2-(benzo[b]thiophen-7-yl)ethyl)-6-chloropyrimidin-4-amine 0.89 (A)290.01 A.1.3. N-(2-(1H-indol-4-yl)ethyl)-6-chloropyrimidin-4-amine 0.80(A) 273.06 A.1.4.6-chloro-N-(2-(1-methyl-1H-indol-4-yl)ethyl)pyrimidin-4-amine 0.87 (A)287.10 A.1.5.6-chloro-N-(2-(4-methylnaphthalen-1-yl)ethyl)pyrimidin-4-amine 0.95 (A)298.10 A.1.6.6-chloro-N-(2-(2-methoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine 0.92 (A)314.09 A.1.7.6-chloro-N-(2-(2-fluoronaphthalen-1-yl)ethyl)pyrimidin-4-amine 0.93 (A)302.05 A.1.8.6-chloro-N-(2-(4-chloronaphthalen-1-yl)ethyl)pyrimidin-4-amine 0.95 (A)317.97 A.1.9.6-chloro-N-(2-(2-ethoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine 0.97 (A)328.07 A.1.10.6-chloro-N-(2-(4-methoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine 0.93 (A)314.05 A.1.11.6-chloro-N-(2-(2-methylnaphthalen-1-yl)ethyl)pyrimidin-4-amine 0.95 (A)298.15 A.1.126-chloro-N-(2-(2-propoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine 0.90 (A)360.08 A.1.136-chloro-N-(2-(4-fluoronaphthalen-1-yl)ethyl)pyrimidin-4-amine 0.93 (A)302.06 A.1.146-chloro-N-(2-(2-(difluoromethoxy)naphthalen-1-yl)ethyl)pyrimidin-4-amine0.94 (A) 350.05 A.1.156-chloro-N-(2-(2-isopropoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine 1.00(A) 342.02 A.1.16.6-chloro-N-(2-(6-methoxyquinolin-5-yl)ethyl)pyrimidin-4-amine 0.58 (A)315.07 A.1.17. N-(2-(1H-indol-7-yl)ethyl)-6-chloropyrimidin-4-amine 0.82(A) 273.06 A.1.18.6-chloro-N-(2-(1-methyl-1H-indol-7-yl)ethyl)pyrimidin-4-amine 0.87 (A)287.08 A.1.19.6-chloro-N-(2-(2-methyl-1H-indol-7-yl)ethyl)pyrimidin-4-amine 0.86 (A)287.08 A.1.20.6-chloro-N-(2-(2-methylbenzo[d]thiazol-7-yl)ethyl)pyrimidin-4-amine 0.82(A) 305.00 A.1.21.N-(2-(benzofuran-7-yl)ethyl)-6-chloropyrimidin-4-amine 0.85 (A) 274.06A.1.22. 6-chloro-N-(2-(7-chloroquinolin-8-yl)ethyl)pyrimidin-4-amine0.88 (A) 319.02 A.1.23.6-chloro-N-(2-(quinolin-8-yl)ethyl)pyrimidin-4-amine 0.62 (A) 285.14A.1.24. N-(2-(benzo[d][1,3]dioxol-4-yl)ethyl)-6-chloropyrimidin-4-amine0.82 (A) 278.09

A.1.25. N-(2-(Benzo[b]thiophen-4-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(benzo[b]thiophen-4-yl)ethan-1-amine and4,6-dichloropyrimidine, and obtained as a yellow oil. LC-MS A:t_(R)=0.89 min; [M+H]⁺=289.93.

A.1.25.1 2-(Benzo[b]thiophen-4-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using (E)-4-(2-nitrovinyl)benzo[b]thiophene, andobtained as a white solid. LC-MS A: t_(R)=0.53 min; [M+H]⁺=178.29.

A.1.25.2 (E)-4-(2-Nitrovinyl)benzo[b]thiophene

The title compound is prepared according to the general procedure Adescribed above, using benzo[b]thiophene-4-carbaldehyde, and obtained asa yellow solid. LC-MS A: t_(R)=0.89 min; no ionization.

A.1.26. N-(2-(2-Bromonaphthalen-1-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(2-bromonaphthalen-1-yl)ethan-1-amine and4,6-dichloropyrimidine. LC-MS A: t_(R)=0.97 min; [M+H]⁺=364.08.

A.1.26.1 2-(2-Bromonaphthalen-1-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using (E)-2-bromo-1-(2-nitrovinyl)naphthalene, andobtained as a RM with 2-(naphthalen-1-yl)ethan-1-amine. LC-MS A:t_(R)=0.60 min; [M+H]⁺=249.96.

A.1.26.2 (E)-2-Bromo-1-(2-nitrovinyl)naphthalene

The title compound is prepared according to the general procedure Adescribed above, using 2-bromo-1-naphthaldehyde, and obtained as ayellow solid. LC-MS A: t_(R)=0.95 min; no ionization.

A.1.27.6-Chloro-N-(2-(5-methoxy-2,3-dihydrobenzofuran-4-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using2-(5-methoxy-2,3-dihydrobenzofuran-4-yl)ethan-1-amine and4,6-dichloropyrimidine, and obtained as an off-white solid. LC-MS A:t_(R)=0.84 min; [M+H]⁺=305.95.

A.1.27.1 2-(5-Methoxy-2,3-dihydrobenzofuran-4-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using(E)-5-methoxy-4-(2-nitrovinyl)-2,3-dihydrobenzofuran, and obtained as ayellow oil. LC-MS A: t_(R)=0.49 min; [M+H]⁺=194.21.

A.1.27.2 (E)-5-Methoxy-4-(2-nitrovinyl)-2,3-dihydrobenzofuran

The title compound is prepared according to the general procedure Adescribed above, using5-methoxy-2,3-dihydro-1-benzofuran-4-carbaldehyde, and obtained as adeep orange solid. LC-MS A: t_(R)=0.87 min; no ionization.

A.1.28.6-Chloro-N-(2-(5-methoxybenzo[d][1,3]dioxol-4-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using2-(5-methoxybenzo[d][1,3]dioxol-4-yl)ethan-1-amine and4,6-dichloropyrimidine, and obtained as a white solid. LC-MS A:t_(R)=0.85 min; [M+H]⁺=308.01.

A.1.28.1 2-(5-Methoxybenzo[d][1,3]dioxol-4-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using(E)-5-methoxy-4-(2-nitrovinyl)benzo[d][1,3]dioxole, and obtained as ayellow oil. LC-MS A: t_(R)=0.49 min; [M+H]⁺=196.16.

A.1.28.2 (E)-5-Methoxy-4-(2-nitrovinyl)benzo[d][1,3]dioxole

The title compound is prepared according to the general procedure Adescribed above, using 5-Methoxy-1,3-benzodioxole-4-carboxaldehyde, andobtained as a deep orange solid. LC-MS A: t_(R)=0.88 min; no ionization.

A.1.29. 6-Chloro-N-(2-(6-methylquinolin-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(6-methylquinolin-5-yl)ethan-1-amine and4,6-dichloropyrimidine, and obtained as a yellow foam. LC-MS A:t_(R)=0.57 min; [M+H]⁺=299.06.

A.1.29.1 2-(6-Methylquinolin-5-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using (E)-6-methyl-5-(2-nitrovinyl)quinoline, andobtained as a brown oil. LC-MS A: t_(R)=0.28 min; [M+H]⁺=187.29.

A.1.29.2 (E)-6-Methyl-5-(2-nitrovinyl)quinoline

The title compound is prepared according to the general procedure Adescribed above, using 6-methyl-5-quinolinecarbaldehyde, and obtained asa yellow solid. LC-MS A: t_(R)=0.59 min; [M+H]⁺⁼215.11.

A.1.30.6-chloro-N-(2-(2,3-dimethylnaphthalen-1-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(2,3-dimethylnaphthalen-1-yl)ethan-1-amine and4,6-dichloropyrimidine, and obtained as a white solid. LC-MS A:t_(R)=0.98 min; [M+H]⁺=312.11.

A.1.30.1 2-(2,3-Dimethylnaphthalen-1-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using (E)-2,3-dimethyl-1-(2-nitrovinyl)naphthalene, andobtained as a pale yellow oil. LC-MS A: t_(R)=0.64 min; [M+H]⁺=200.16.

A.1.30.2 (E)-2,3-Dimethyl-1-(2-nitrovinyl)naphthalene

The title compound is prepared according to the general procedure Adescribed above, using 2,3-dimethylnaphthalene-1-carbaldehyde, andobtained as a deep yellow solid. LC-MS A: t_(R)=0.97 min; no ionization.

A.1.31. 6-Chloro-N-(2-(3-methoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(3-methoxynaphthalen-1-yl)ethan-1-amine and4,6-dichloropyrimidine, and obtained as a white solid. LC-MS A:t_(R)=0.92 min; [M+H]⁺=314.04.

A.1.31.1 2-(3-Methoxynaphthalen-1-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using (E)-3-methoxy-1-(2-nitrovinyl)naphthalene, andobtained as a pale yellow oil. LC-MS A: t_(R)=0.58 min; [M+H]⁺=202.15.

A.1.31.2 (E)-3-Methoxy-1-(2-nitrovinyl)naphthalene

The title compound is prepared according to the general procedure Adescribed above, using 3-methoxy-1-naphthaldehyde, and obtained as adeep yellow solid. LC-MS A: t_(R)=0.93 min; no ionization.

A.1.32.6-Chloro-N-(2-(5-ethoxybenzo[d][1,3]dioxol-4-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using2-(5-methoxybenzo[d][1,3]dioxol-4-yl)ethan-1-amine and4,6-dichloropyrimidine, and obtained as a white solid. LC-MS A:t_(R)=0.90 min; [M+H]⁺=321.93.

A.1.32.1 2-(5-ethoxybenzo[d][1,3]dioxol-4-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using(E)-5-methoxy-4-(2-nitrovinyl)benzo[d][1,3]dioxole, and obtained as acolorless oil. LC-MS A: t_(R)=0.55 min; [M+H]⁺=210.13.

A.1.32.2 (E)-5-ethoxy-4-(2-nitrovinyl)benzo[d][1,3]dioxole

The title compound is prepared according to the general procedure Adescribed above, using 5-ethoxy-1,3-benzodioxole-4-carboxaldehyde, andobtained as a orange solid. LC-MS A: t_(R)=0.92 min; no ionization.

A.1.33.6-Chloro-N-(2-(1,2,3-trimethyl-1H-indol-7-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(1,2,3-trimethyl-1H-indol-7-yl)ethan-1-amineand 4,6-dichloropyrimidine, and obtained as an off-white solid. LC-MS A:t_(R)=0.95 min; [M+H]⁺=315.08.

A.1.33.1 2-(1,2,3-Trimethyl-1H-indol-7-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using (E)-1,2,3-trimethyl-7-(2-nitrovinyl)-1H-indole,and obtained as a yellow oil. LC-MS A: t_(R)=0.58 min; [M+H]⁺=203.22.

A.1.33.2 (E)-1,2,3-Trimethyl-7-(2-nitrovinyl)-1H-indole

The title compound is prepared according to the general procedure Adescribed above, using 1,2,3-trimethyl-1H-indole-7-carbaldehyde, andobtained as a red solid. LC-MS A: t_(R)=0.96 min; [M+H]⁺=231.13.

A.1.34. 6-Chloro-N-(2-(7-methoxyquinolin-8-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(7-methoxyquinolin-8-yl)ethan-1-amine and4,6-dichloropyrimidine, and obtained as an orange solid. LC-MS A:t_(R)=0.59 min; [M+H]⁺=315.05.

A.1.34.1 2-(7-Methoxyquinolin-8-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using (E)-7-methoxy-8-(2-nitrovinyl)quinoline, andobtained as an orange oil. LC-MS A: t_(R)=0.36 min; [M+H]⁺=203.16.

A.1.34.2 (E)-7-Methoxy-8-(2-nitrovinyl)quinoline

The title compound is prepared according to the general procedure Adescribed above, using 7-methoxy-8-quinolinecarboxaldehyde, and obtainedas an orange solid. LC-MS A: t_(R)=0.86 min; [M+H]⁺=231.10.

A.1.35.6-Chloro-N-(2-(2,5-dimethoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(2,5-dimethoxynaphthalen-1-yl)ethan-1-amine and4,6-dichloropyrimidine, and obtained as white foam. LC-MS A: t_(R)=0.94min; [M+H]⁺=344.07.

A.1.35.1 2-(2,5-dimethoxynaphthalen-1-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using (E)-2,5-dimethoxy-1-(2-nitrovinyl)naphthalene,and obtained as a pale yellow oil. LC-MS A: t_(R)=0.61 min;[M+H]⁺=232.14.

A.1.35.2 (E)-2,5-dimethoxy-1-(2-nitrovinyl)naphthalene

The title compound is prepared according to the general procedure Adescribed above, using 2,5-dimethoxy-1-naphthaldehyde, and obtained asan orange solid. LC-MS A: t_(R)=0.95 min; [M+H]⁺⁼260.16.

A.1.35.3 2,5-Dimethoxy-1-naphthaldehyde

To a solution of titanium(IV) chloride (1.0 M in DCM; 11.7 mL; 2.2equiv.) in DCM (40 mL) at 0° C. is added dropwise a solution ofdichloromethyl methyl ether (672 mg; 1.1 equiv.) in DCM (3 mL). Asolution of 1,6-dimethoxynaphthalene (1.00 g; 5.31 mmol) in DCM (20 mL)is then added dropwise, and the RM is stirred at 0° C. for 5 min. and atRT for 3 h. It is then quenched with 1 M aq. HCl (75 mL). The organiclayer is separated and washed successively with water, sat. NaHCO₃solution, and brine, dried over MgSO₄, filtered, and concentrated underreduced pressure. Purification by FC (Hept/DCM 1:9 to DCM) affords thetitle compound as an orange oil (601 mg, 52%). LC-MS A: t_(R)=0.87 min;[M+H]⁺=217.07.

A.1.36.6-Chloro-N-(2-(2,3-dimethoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(2,3-dimethoxynaphthalen-1-yl)ethan-1-amine and4,6-dichloropyrimidine, and obtained as a brown oil. LC-MS A: t_(R)=0.93min; [M+H]⁺=344.05.

A.1.36.1 2-(2,3-Dimethoxynaphthalen-1-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using (E)-2,3-dimethoxy-1-(2-nitrovinyl)naphthalene,and obtained as a yellow oil. LC-MS A: t_(R)=0.59 min; [M+H]⁺=232.07.

A.1.36.2 (E)-2,3-dimethoxy-1-(2-nitrovinyl)naphthalene

The title compound is prepared according to the general procedure Adescribed above, using 2,3-Dimethoxy-1-naphthaldehyde, and obtained asan orange solid. LC-MS A: t_(R)=0.91 min; no ionization.

A.1.37.6-Chloro-N-(2-(4-(difluoromethyl)naphthalen-1-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using2-(4-(difluoromethyl)naphthalen-1-yl)ethan-1-amine hydrochloride and4,6-dichloropyrimidine, and obtained as an off-white solid. LC-MS A:t_(R)=0.90 min; [M+H]⁺=334.00.

A.1.37.1 2-(4-(Difluoromethyl)naphthalen-1-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the general procedure Edescribed above, using tert-butyl(2-(4-(difluoromethyl)naphthalen-1-yl)ethyl)carbamate, and obtained as apale pink solid. LC-MS A: t_(R)=0.60 min; [M+H]⁺=222.09.

A.1.37.2 Tert-butyl(2-(4-(difluoromethyl)naphthalen-1-yl)ethyl)carbamate

The title compound is prepared according to the general procedure Cdescribed above, using 1-bromo-4-(difluoromethyl)naphthalene, andobtained as an orange solid. LC-MS A: t_(R)=0.96 min; no ionization.

A.1.38. 6-Chloro-N-(2-(2-methylbenzofuran-7-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(2-methylbenzofuran-7-yl)ethan-1-aminehydrochloride and 4,6-dichloropyrimidine, and obtained as an off-whitesolid. LC-MS A: t_(R)=0.91 min; [M+H]⁺=288.10.

A.1.38.1 2-(2-Methylbenzofuran-7-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the general procedure Edescribed above, using tert-butyl(2-(2-methylbenzofuran-7-yl)ethyl)carbamate, and obtained as a paleyellow solid. LC-MS A: t_(R)=0.54 min; [M+H]⁺=176.32.

A.1.38.2 Tert-butyl (2-(2-methylbenzofuran-7-yl)ethyl)carbamate

The title compound is prepared according to the general procedure Cdescribed above, using 7-bromo-2-methyl-1-benzofuran, and obtained as ayellow oil. LC-MS A: t_(R)=0.93 min; [M+H]⁺=276.11.

A.1.39.6-Chloro-N-(2-(1,5-dimethyl-1H-indazol-4-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(1,5-dimethyl-1H-indazol-4-yl)ethan-1-aminehydrochloride and 4,6-dichloropyrimidine, and obtained as a white solid.LC-MS A: t_(R)=0.83 min; [M+H]⁺=302.15.

A.1.39.1 2-(1,5-Dimethyl-1H-indazol-4-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the general procedure Edescribed above, using tert-butyl(2-(1,5-dimethyl-1H-indazol-4-yl)ethyl)carbamate, and obtained as awhite solid. LC-MS A: t_(R)=0.50 min; [M+H]⁺=231.26.

A.1.39.2 Tert-butyl (2-(1,5-dimethyl-1H-indazol-4-yl)ethyl)carbamate

The title compound is prepared according to the general procedure Cdescribed above, using 4-bromo-1,5-dimethyl-1H-indazole, and obtained asa white solid. LC-MS A: t_(R)=0.87 min; [M+H]⁺=290.16.

A.1.40. N-(2-(2-Aminonaphthalen-1-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 1-(2-aminoethyl)naphthalen-2-amine hydrochlorideand 4,6-dichloropyrimidine, and obtained as a brown solid. LC-MS A:t_(R)=0.75 min; [M+H]⁺=299.07.

A.1.40.1 1-(2-Aminoethyl)naphthalen-2-amine hydrochloride

The title compound is prepared according to the general procedure Edescribed above, using tert-butyl(2-(2-aminonaphthalen-1-yl)ethyl)carbamate, and obtained as a blacksolid. LC-MS A: t_(R)=0.48 min; [M+H]⁺=187.21.

A.1.40.2 Tert-butyl (2-(2-aminonaphthalen-1-yl)ethyl)carbamate

The title compound is prepared according to the general procedure Cdescribed above, using 1-bromonaphtalen-2-amine, and obtained as a blacksolid. LC-MS A: t_(R)=0.77 min; [M+H]⁺=287.17.

A.1.41. 6-Chloro-N-(2-(6-methylisoquinolin-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(6-methylisoquinolin-5-yl)ethan-1-aminehydrochloride and 4,6-dichloropyrimidine, and obtained as an orangesolid. LC-MS A: t_(R)=0.56 min; [M+H]⁺=299.05.

A.1.41.1 2-(6-Methylisoquinolin-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the general procedure Edescribed above, using tert-butyl(2-(6-methylisoquinolin-5-yl)ethyl)carbamate, and obtained as a paleyellow solid. LC-MS A: t_(R)=0.30 min; [M+H]⁺=187.28.

A.1.41.2 Tert-butyl (2-(6-methylisoquinolin-5-yl)ethyl)carbamate

The title compound is prepared according to the general procedure Cdescribed above, using 5-bromo-6-methylisoquinoline, and obtained as apale yellow oil. LC-MS A: t_(R)=0.62 min; [M+H]⁺=287.17.

A.1.42.6-Chloro-N-(2-(1,2-dimethyl-1H-indol-7-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(1,2-dimethyl-1H-indol-7-yl)ethan-1-amine and4,6-dichloropyrimidine, and obtained as a yellow solid. LC-MS A:t_(R)=0.90 min; [M+H]⁺=301.06.

A.1.42.1 2-(1,2-Dimethyl-1H-indol-7-yl)ethan-1-amine

The title compound is prepared according to the general procedure Bdescribed above, using (E)-1,2-dimethyl-7-(2-nitrovinyl)-1H-indole, andobtained as a yellow oil. LC-MS A: t_(R)=0.57 min; [M+H]⁺=189.25.

A.1.42.2 (E)-1,2-Dimethyl-7-(2-nitrovinyl)-1H-indole

The title compound is prepared according to the general procedure Adescribed above, using 1,2-dimethyl-1H-indole-7-carbaldehyde, andobtained as an orange solid. LC-MS A: t_(R)=0.91 min; [M+H]⁺=217.12.

A.1.43.6-Chloro-N-(2-(2-(difluoromethyl)naphthalen-1-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using2-(2-(difluoromethyl)naphthalen-1-yl)ethan-1-amine hydrochloride and4,6-dichloropyrimidine, and obtained as a pale yellow solid. LC-MS A:t_(R)=0.95 min; [M+H]⁺=334.03.

A.1.43.1 2-(2-(difluoromethyl)naphthalen-1-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the general procedure Edescribed above, using tert-butyl(2-(2-(difluoromethyl)naphthalen-1-yl)ethyl)carbamate, and obtained as apale yellow solid. LC-MS A: t_(R)=0.61 min; [M+H]⁺=222.11.

A.1.43.2 Tert-butyl (2-(6-methylisoquinolin-5-yl)ethyl)carbamate

The title compound is prepared according to the general procedure Cdescribed above, using tert-butyl(2-(2-(difluoromethyl)naphthalen-1-yl)ethyl)carbamate, and obtained as adeep yellow solid. LC-MS A: t_(R)=0.98 min; no ionization.

A.1.44. 1-(2-((6-Chloropyrimidin-4-yl)amino)ethyl)-2-naphthonitrile

The title compound is prepared according to the general procedure Edescribed above, using tert-butyl(6-chloropyrimidin-4-yl)(2-(2-cyanonaphthalen-1-yl)ethyl)carbamate, andobtained as a beige solid. LC-MS A: t_(R)=0.88 min; [M+H]⁺=309.02.

A.1.44.1 Tert-butyl(6-chloropyrimidin-4-yl)(2-(2-cyanonaphthalen-1-yl)ethyl)carbamate

Tert-butyl (2-(2-cyanonaphthalen-1-yl)ethyl)carbamate (350 mg, 1.18mmol) is dissolved in dry dioxane (6 mL). The solution is cooled down to15° C., and sodium hydride (189 mg, 4.72 mmol) is added portionwise.After stirring at rt for 15 min, 4,6-dichloropyrimidine (440 mg, 2.95mmol is added to the suspension at 15° C. The RM is heated up to 90° C.and stirred overnight. The RM is carefully quenched at 0° C. with waterthen extracted with EtOAc, the organic layer is washed with brine, driedover MgSO₄, filtered and concentrated. Purification by FC (Hept/EtOAc10:0 to 7:3) affords the tuitle compound as a white solid (0.370 g,77%). LC-MS A: t_(R)=1.08 min; [M+H]⁺=409.15.

A.1.44.2 Tert-butyl (2-(2-cyanonaphthalen-1-yl)ethyl)carbamate

The title compound is prepared according to the general procedure Cdescribed above, using 1-bromonaphthalene-2-carbonitrile, and obtainedas a beige solid. LC-MS A: t_(R)=0.92 min; [M+H]⁺=297.11.

A.1.45.6-Chloro-N-(2-(7-methoxy-4-methylquinolin-8-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the general procedure Fdescribed above, using 2-(7-methoxy-4-methylquinolin-8-yl)ethan-1-aminehydrochloride and 4,6-dichloropyrimidine, and obtained as a beige solid.LC-MS A: tR=0.59 min; [M+H]⁺=329.05.

A.1.45.1 2-(7-Methoxy-4-methylquinolin-8-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the general procedure Edescribed above, using tert-butyl(2-(7-methoxy-4-methylquinolin-8-yl)ethyl)carbamate, and obtained as ayellow solid. LC-MS A: t_(R)=0.36 min; [M+H]⁺=217.15.

A.1.45.2 Tert-butyl (2-(7-methoxy-4-methylquinolin-8-yl)ethyl)carbamate

The title compound is prepared according to the general procedure Cdescribed above, using 8-bromo-7-methoxy-4-methylquinoline, and obtainedas a yellow oil. LC-MS A: t_(R)=0.63 min; [M+H]⁺=317.14.

A.1.45.3 8-Bromo-7-methoxy-4-methylquinoline

To a stirred solution of 7-methoxy-4-methylquinoline (1.00 g, 5.77 mmol)in DCM (25 mL) is added NBS (1.23 g, 6.91 mmol). The resultingsuspension is stirred for 3 d at RT. The RM is diluted with DCM andwashed with saturated aqueous NaHCO₃ and brine, dried over MgSO₄ andthen purified by FC to give the desired product as a yellow solid (1.118g, 77%). LC-MS A: t_(R)=0.51 min; [M+H]⁺=252.00.

A.1.46. N-(2-(4-bromonaphthalen-1-yl)ethyl)-6-iodopyrimidin-4-amine

The title compound is obtained from2-(4-bromonaphthalen-1-yl)ethan-1-amine and 4,6-diiodopyrimidine,following the general procedure F. LC-MS B: t_(R)=1.02 min;[M+H]⁺=453.95.

A.1.46.1. 2-(4-Bromonaphthalen-1-yl)ethan-1-amine

The title compound is obtained from(E)-1-bromo-4-(2-nitrovinyl)naphthalene, following the general procedureB. LC-MS B: t_(R)=0.67 min; [M+H]⁺=250.24.

A.1.46.2. (E)-1-bromo-4-(2-nitrovinyl)naphthalene

The title compound is obtained from 4-bromo-1-naphthaldehyde, followingthe general procedure A. LC-MS B: t_(R)=1.06 min; no ionization. ¹H NMR(400 MHz, d6-DMSO) δ: 8.84 (d, J=13.3 Hz, 1H), 8.39 (d, J=7.9 Hz, 1H),8.28 (m, 2H), 8.02 (s, 2H), 7.81 (m, 2H).

A.1.47. 6-chloro-N-(2-(5-fluoronaphthalen-1-yl)ethyl)pyrimidin-4-amine

The title compound is obtained from2-(5-fluoronaphthalen-1-yl)ethan-1-amine hydrochloride and4,6-dichloropyrimidine, following the general procedure F. LC-MS B:t_(R)=1.02 min; [M+H]⁺=302.16.

A.1.47.1. 2-(5-fluoronaphthalen-1-yl)ethan-1-amine hydrochloride

The title compound is obtained from tert-butyl(2-(5-fluoronaphthalen-1-yl)ethyl)carbamate, following the generalprocedure E. LC-MS B: t_(R)=0.61 min; [M+H]⁺=190.39.

A.1.47.2. Tert-butyl (2-(5-fluoronaphthalen-1-yl)ethyl)carbamate

The title compound is obtained from 1-bromo-5-fluoronaphthalene,following the general procedure C. LC-MS B: t_(R)=1.05 min;[M+H—CH₃]⁺=275.24.

A.1.48.6-Chloro-N-(2-(6-fluorobenzo[b]thiophen-4-yl)ethyl)pyrimidin-4-amine

The title compound is obtained from2-(6-fluorobenzo[b]thiophen-4-yl)ethan-1-amine hydrochloride and4,6-dichloropyrimidine, following the general procedure F. LC-MS B:t_(R)=1.00 min; [M+H]⁺=308.11.

A.1.48.1. 2-(6-Fluorobenzo[b]thiophen-4-yl)ethan-1-amine hydrochloride

The title compound is obtained from tert-butyl(2-(6-fluorobenzo[b]thiophen-4-yl)ethyl)carbamate, following the generalprocedure E. LC-MS B: t_(R)=0.59 min; [M+H]⁺=196.27.

A.1.48.2. Tert-butyl (2-(6-fluorobenzo[b]thiophen-4-yl)ethyl)carbamate

The title compound is obtained from 4-bromo-6-fluorobenzo[b]thiophene,following the general procedure C. LC-MS B: t_(R)=1.04 min;[M+H—CH₃]⁺=281.18.

A.1.48.3. 4-Bromo-6-fluorobenzo[b]thiophene

A mixture of 4-bromo-6-fluorobenzo[b]thiophene-2-carboxylic acid (500mg, 1.82 mmol), copper(I) oxide (65 mg, 0.454 mmol) and DMF (9 mL) isheated at 140° C. overnight under N₂. It is then cooled to RT andfiltered over Whatman filter, washing with EtOAc. The filtrate is washedtwice with a solution of NH₄OH then the combined aqueous layers areextracted with EtOAc (2×). The combined organic layers are washed withadditional water, then dried over MgSO₄ and concentrated to dryness. Theresidue is purified by FC (Hept:EtOAc 1:0 to 9:1) to afford the productas a white solid (254 mg, 60%). LC-MS B: t_(R)=1.02 min; no ionization.

A.1.49. 6-Chloro-N-(2-(3-fluoronaphthalen-1-yl)ethyl)pyrimidin-4-amine

The title compound is obtained from2-(3-fluoronaphthalen-1-yl)ethan-1-amine and 4,6-dichloropyrimidine,following the general procedure F. LC-MS B: t_(R)=1.02 min;[M+H]⁺=302.19.

A.1.49.1. 2-(3-fluoronaphthalen-1-yl)ethan-1-amine

The title compound is obtained from(E)-3-fluoro-1-(2-nitrovinyl)naphthalene, following the generalprocedure B. LC-MS B: t_(R)=0.60 min; [M+H]⁺=190.34.

A.1.49.2. (E)-3-fluoro-1-(2-nitrovinyl)naphthalene

The title compound is obtained from 3-fluoronaphthalene-1-carbaldehyde,following the general procedure A. LC-MS B: t_(R)=0.60 min;[M+H]⁺=190.34.

A.1.50. 6-Chloro-N-(2-(5-methylnaphthalen-1-yl)ethyl)pyrimidin-4-amine

The title compound is obtained from2-(5-methylnaphthalen-1-yl)ethan-1-amine hydrochloride and4,6-dichloropyrimidine, following the general procedure F. LC-MS B:t_(R)=1.04 min; [M+H]⁺=298.18.

A.1.50.1. 2-(5-Methylnaphthalen-1-yl)ethan-1-amine hydrochloride

The title compound is obtained from tert-butyl(2-(5-methylnaphthalen-1-yl)ethyl)carbamate, following the generalprocedure E. LC-MS B: t_(R)=0.63 min; [M+H]⁺=186.43.

A.1.50.2. Tert-butyl (2-(5-methylnaphthalen-1-yl)ethyl)carbamate

The title compound is obtained from 1-bromo-5-methylnaphthalene,following the general procedure C. LC-MS B: t_(R)=1.07 min;[M+H—CH₃]+=271.31.

A.1.51.6-Chloro-N-(2-(5-methoxybenzo[b]thiophen-4-yl)ethyl)pyrimidin-4-amine

The title compound is obtained from2-(5-methoxybenzo[b]thiophen-4-yl)ethan-1-amine hydrochloride and4,6-dichloropyrimidine, following the general procedure F. LC-MS B:t_(R)=1.00 min; [M+H]⁺=320.14.

A.1.51.1. 2-(5-Methoxybenzo[b]thiophen-4-yl)ethan-1-amine hydrochloride

The title compound is obtained from tert-butyl(2-(5-methoxybenzo[b]thiophen-4-yl)ethyl)carbamate, following thegeneral procedure E. LC-MS B: t_(R)=0.60 min; [M+H]⁺=208.26.

A.1.51.2. Tert-butyl (2-(5-methoxybenzo[b]thiophen-4-yl)ethyl)carbamate

The title compound is obtained from 4-bromo-5-methoxybenzo[b]thiophene,following the general procedure C. LC-MS B: t_(R)=1.04 min;[M+H]⁺=308.19.

A.1.51.3. 4-Bromo-5-methoxybenzo[b]thiophene

Iodomethane (0.083 mL, 1.32 mmol) is added to a RT solution of4-bromo-1-benzothiophen-5-ol (300 mg, 1.26 mmol) and K₂CO₃ (261 mg, 1.89mmol) in DMF (5 mL). The RM is stirred at 60° C. for 1 h, then cooled toRT and partitioned between water and EtOAc. The organic extracts arewashed with brine, dried (MgSO₄), and concentrated under reducedpressure, affording the title compound as a yellow oil (330 mg, quant.).LC-MS B: t_(R)=0.99 min; no ionization.

A.1.52.6-Chloro-N-(2-(5-ethoxybenzo[b]thiophen-4-yl)ethyl)pyrimidin-4-amine

The title compound is obtained from2-(5-ethoxybenzo[b]thiophen-4-yl)ethan-1-amine hydrochloride and4,6-dichloropyrimidine, following the general procedure F. LC-MS B:t_(R)=1.05 min; [M+H]⁺=334.18.

A.1.52.1. 2-(5-Ethoxybenzo[b]thiophen-4-yl)ethan-1-amine hydrochloride

The title compound is obtained from tert-butyl(2-(5-ethoxybenzo[b]thiophen-4-yl)ethyl)carbamate, following the generalprocedure E. LC-MS B: t_(R)=0.66 min; [M+H]⁺=222.27.

A.1.52.2. Tert-butyl (2-(5-ethoxybenzo[b]thiophen-4-yl)ethyl)carbamate

The title compound is obtained from 4-bromo-5-ethoxybenzo[b]thiophene,following the general procedure C. LC-MS B: t_(R)=1.08 min;[M+H]⁺=321.95.

A.1.52.3. 4-Bromo-5-ethoxybenzo[b]thiophene

Iodoethane (0.107 mL, 1.32 mmol) is added to a RT solution of4-bromo-1-benzothiophen-5-ol (300 mg, 1.26 mmol) and K₂CO₃ (261 mg, 1.89mmol) in DMF (5 mL). The RM is stirred at 60° C. overnight, then cooledto RT and partitioned between water and EtOAc. The organic extracts arewashed with brine, dried (MgSO₄), and concentrated under reducedpressure. The residue is purified by FC (heptane/EtOAc, from 1:0 to7:3), affording the title compound as a colorless oil (302 mg, 93%).LC-MS B: t_(R)=1.04 min; no ionization.

A.1.53.N-(2-(2-bromo-4-fluoronaphthalen-1-yl)ethyl)-6-iodopyrimidin-4-amine

The title compound is obtained from2-(2-bromo-4-fluoronaphthalen-1-yl)ethan-1-amine and4,6-diiodopyrimidine, following the general procedure F. LC-MS B:t_(R)=1.04 min; [M+H]⁺=471.89.

A.1.53.1. 2-(2-Bromo-4-fluoronaphthalen-1-yl)ethan-1-amine

The title compound is obtained from(E)-2-bromo-4-fluoro-1-(2-nitrovinyl)naphthalene, following the generalprocedure B. LC-MS B: t_(R)=0.69 min; [M+H]⁺=268.18.

A.1.53.2. (E)-2-Bromo-4-fluoro-1-(2-nitrovinyl)naphthalene

The title compound is obtained from 2-bromo-4-fluoro-1-naphtaldehyde,following the general procedure A. LC-MS B: t_(R)=1.09 min; noionization. ¹H NMR (400 MHz, d6-DMSO) δ: 8.76 (d, J=13.3 Hz, 1H), 8.42(m, 2H), 8.35 (d, J=13.3 Hz, 1H), 8.16-8.18 (m, 1H), 7.80-7.83 (m, 2H).

A.1.54.6-Chloro-N-(2-(6-methoxy-1-methyl-1H-indol-7-yl)ethyl)pyrimidin-4-amine

The title compound is obtained from2-(6-methoxy-1-methyl-1H-indol-7-yl)ethan-1-amine hydrochloride and4,6-dichloropyrimidine, following the general procedure F. LC-MS B:t_(R)=0.96 min; [M+H]⁺=317.21.

A.1.54.1. 2-(6-Methoxy-1-methyl-1H-indol-7-yl)ethan-1-aminehydrochloride

The title compound is obtained from tert-butyl(2-(6-methoxy-1-methyl-1H-indol-7-yl)ethyl)carbamate, following thegeneral procedure E. LC-MS B: t_(R)=0.51 min; no ionization.

A.1.54.2. Tert-butyl(2-(6-methoxy-1-methyl-1H-indol-7-yl)ethyl)carbamate

The title compound is obtained from 7-bromo-6-methoxy-1-methyl-1H-indolefollowing the general procedure C. LC-MS B: t_(R)=1.01 min;[M+H]⁺=305.24.

A.1.54.3. 7-Bromo-6-methoxy-1-methyl-1H-indole

A solution of 7-bromo-6-methoxy-1H-indole (1275 mg, 3.64 mmol) in DMF(20 mL) is cooled at 0° C. Sodium hydride (60% suspension in oil, 262mg, 6.56 mmol) is added portionwise, and the RM is stirred at RT for 45min. Iodomethane (0.454 mL, 7.29 mmol) is added dropwise, and the RM isstirred at RT overnight. It is then quenched carefully by pouring itinto sat. aq. NH₄Cl, and extracted with DCM (3×). The combined organicextracts are washed with brine dried (MgSO₄) and concentrated undervacuum. The residue is purified by FC (Hept:EtOAc 1:0 to 17:3),affording the title compound as yellow oil (260 mg, 55%). LC-MS B:t_(R)=0.96 min; [M+H]⁺=240.15.

A.1.54.4. 7-Bromo-6-methoxy-1H-indole

2-Bromo-1-methoxy-3-nitrobenzene (2500 mg, 10.8 mmol) is dissolved inTHF (200 mL) and cooled at −78° C. Vinylmagnesium bromide (1M in THF,37.7 mL, 37.7 mmol) is added dropwise to the mixture. The reaction isstirred at −78° C. overnight allowing the mixture to reach RT. 50 mL ofa saturated NH₄Cl solution is slowly added. The mixture is diluted withwater and extracted with DCM. The organic layer is dried over MgSO₄ andconcentrated. The residue is purified by FC (Hept:DCM 1:0 to 1:1),affording the title compound as a pale orange solid (443 mg, 18%). LC-MSB: t_(R)=0.86 min; no ionization.

A.1.55.6-Chloro-N-(2-(5-methoxy-1-methyl-1H-indol-4-yl)ethyl)pyrimidin-4-amine

The title compound is obtained from2-(5-methoxy-1-methyl-1H-indol-4-yl)ethan-1-amine hydrochloride and4,6-dichloropyrimidine, following the general procedure F. LC-MS B:t_(R)=0.96 min; [M+H]⁺=317.21.

A.1.55.1. 2-(5-Methoxy-1-methyl-1H-indol-4-yl)ethan-1-aminehydrochloride

The title compound is obtained from tert-butyl(2-(5-methoxy-1-methyl-1H-indol-4-yl)ethyl)carbamate, following thegeneral procedure E. LC-MS B: t_(R)=0.56 min; [M+H]⁺=205.34.

A.1.55.2. Tert-butyl(2-(5-methoxy-1-methyl-1H-indol-4-yl)ethyl)carbamate

The title compound is obtained from 4-bromo-5-methoxy-1-methyl-1H-indolefollowing the general procedure C. LC-MS B: t_(R)=1.00 min;[M+H]⁺=305.23.

A.1.55.3. 4-Bromo-5-methoxy-1-methyl-1H-indole

NaH (60% in oil, 75.6 mg, 3.15 mmol) is added to a RT solution of4-bromo-5-methoxy-1H-indole (500 mg, 2.1 mmol) in DMF (5 mL). The RM isstirred at RT for 20 min and iodomethane (0.145 mL, 2.31 mmol) is added.The RM is then stirred overnight at RT. Water is added, and the mixtureis extracted twice with EtOAc. Combined organic layers are washed withbrine, dried (MgSO₄), filtered and concentrated under reduced pressure.The residue is purified by FC (heptane:EtOAc, 1:0 to 7:3), affording thetitle compound as a beige solid (426 mg, 84%). LC-MS B: t_(R)=0.94 min;[M+H]⁺=241.91.

A.1.56.6-Chloro-N-(2-(1,5-dimethyl-1H-indol-4-yl)ethyl)pyrimidin-4-amine

The title compound is obtained from2-(1,5-dimethyl-1H-indol-4-yl)ethan-1-amine hydrochloride and4,6-dichloropyrimidine, following the general procedure F. LC-MS B:t_(R)=0.98 min; [M+H]⁺=301.19.

A.1.56.1. 2-(1,5-Dimethyl-1H-indol-4-yl)ethan-1-amine hydrochloride

The title compound is obtained from tert-butyl(2-(1,5-dimethyl-1H-indol-4-yl)ethyl)carbamate, following the generalprocedure E. LC-MS B: t_(R)=0.58 min; [M+H]⁺=189.37.

A.1.56.2. Tert-butyl (2-(1,5-dimethyl-1H-indol-4-yl)ethyl)carbamate

The title compound is obtained from 4-bromo-1,5-dimethyl-1H-indolefollowing the general procedure C. LC-MS B: t_(R)=1.03 min;[M+H]⁺=289.25.

A.1.56.3. 4-Bromo-1,5-dimethyl-1H-indole

NaH (60% in oil, 81.4 mg, 3.39 mmol) is added to a RT solution of4-bromo-5-methyl-1H-indole (500 mg, 2.26 mmol) in DMF (5 mL). It isstirred at RT for 20 min and iodomethane (0.156 mL, 2.49 mmol) is added.The RM is stirred at RT for 3 h. Water is added, and the mixture isextracted twice with EtOAc. Combined organic layers are washed withbrine, dried (MgSO₄), filtered and concentrated under reduced pressure.The residue is purified by FC (heptane:EtOAc, 1:0 to 7:3), affording thetitle compound as a beige solid (464 mg, 92%). LC-MS B: t_(R)=1.02 min;[M+H]⁺=226.2.

A.1.57.N-(2-(4-bromo-1-methyl-1H-indol-7-yl)ethyl)-6-iodopyrimidin-4-amine

The title compound is obtained from2-(4-bromo-1-methyl-1H-indol-7-yl)ethan-1-amine and4,6-diiodopyrimidine, following the general procedure F. LC-MS B:t_(R)=0.98 min; [M+H]⁺=456.94.

A.1.57.1. 2-(4-Bromo-1-methyl-1H-indol-7-yl)ethan-1-amine

The title compound is obtained from(E)-4-bromo-1-methyl-7-(2-nitrovinyl)-1H-indole, following the generalprocedure B. LC-MS B: t_(R)=0.64 min; [M+H]⁺=253.15.

A.1.57.2. (E)-4-Bromo-1-methyl-7-(2-nitrovinyl)-1H-indole

The title compound is obtained from4-bromo-1-methyl-1H-indole-7-carbaldehyde, following the generalprocedure A. LC-MS B: t_(R)=1.03 min; [M+H]⁺=281.04.

A.1.57.3. 4-Bromo-1-methyl-1H-indole-7-carbaldehyde

Into an ice-cold solution of methyl4-bromo-1-methyl-1H-indole-7-carboxylate (1009 mg, 3.61 mmol) in THF (15mL) is added dropwise a solution of LiAIH4 (2M in THF, 2.17 mL, 4.34mmol), and the RM is stirred for 2 h allowing the temperature to reachRT. The RM is cooled again at 0° C., 165 μL of water, 0.330 mL of 10%aqueous sodium hydroxide solution and 0.495 mL of water are addeddropwise one after another and the RM is stirred for 30 min at RT. It isfiltered over Celite, rinsing with DCM and concentrated under reducedpressure. The residue is taken up in THF (40 mL), MnO₂ (3769 mg, 43.4mmol) is added portionwise and the RM is stirred at RT for 24 h. It isthen filtered over Celite, the cake is rinsed with EtOAc and thefiltrate is concentrated under reduced pressure, affording the titlecompound as an orange oil (844 mg, 98%). LC-MS B: t_(R)=0.94 min;[M+H]⁺=238.12.

A.1.58.1-(2-((6-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-5-methoxy-2-naphthonitrile

Tert-butyl(6-chloropyrimidin-4-yl)(2-(2-cyano-8-fluoro-5-methoxynaphthalen-1-yl)ethyl)carbamate(83 mg, 0.174 mmol) is suspended in HCl (4N in dioxane, 4.35 mL, 17.4mmol) and stirred overnight at 60° C. The mixture is evaporated undervacuum and well dried under high vacuum, affording the title compound asa white solid 56 mg, 90%). LC-MS B: t_(R)=0.97 min; [M+H]⁺=357.18.

A.1.58.1. Tert-butyl(6-chloropyrimidin-4-yl)(2-(2-cyano-8-fluoro-5-methoxynaphthalen-1-yl)ethyl)carbamate

To a solution of tert-butyl(2-(2-cyano-8-fluoro-5-methoxynaphthalen-1-yl)ethyl)carbamate (100 mg,0.267 mmol) in dioxane (6 mL) at RT is added portionwise NaH (60%suspension in oil, 48.1 mg, 1.2 mmol). The RM is stirred at RT for 5min, then 4-chloro-6-fluoropyrimidine (85.7 mg, 0.614 mmol) is addedportionwise and the RM is refluxed for 20 h. Under ice bath cooling andN₂ the mixture is carefully quenched by dropwise addition of 5 mL water.The main part of the dioxane is removed under vacuum, then it isextracted once with DCM then twice with EtOAc. The organic layer iswashed with 10 mL of brine, dried over MgSO₄, filtered and concentrated.The residue is purified by FC (Hept/DCM 1:0 to 0:1), affording the titlecompound as a white solid (83 mg, 66%). LC-MS B: t_(R)=1.32 min;[M+H]⁺=457.26.

A.1.58.2. Tert-butyl(2-(2-cyano-8-fluoro-5-methoxynaphthalen-1-yl)ethyl)carbamate

A mixture of 2-cyano-8-fluoro-5-methoxynaphthalen-1-yltrifluoromethanesulfonate (677 mg, 1.86 mmol), potassium tert-butylN-[2-(trifluoroboranuidyl)ethyl]carbamate (514 mg, 2.05 mmol), andCs₂CO₃ (1 M, 5.6 mL, 5.58 mmol) in toluene (20 mL) is degassed with N₂,then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (152 mg, 0.186 mmol) is added and the RM isrefluxed for 2 h. It is allowed to cool to RT, water and EtOAc areadded, and the resulting mixture is filtered, rinsed with EtOAc andextracted. The combined organic layers are dried over MgSO₄, filtered,and concentrated to dryness under reduced pressure. The residue ispurified by FC (Hept:EtOAc 1:0 to 1:1), affording the title compound asa beige solid (410 mg, 64%). LC-MS B: t_(R)=1.05 min; [M-tBu]⁺=289.21.

A.1.58.3. 2-Cyano-8-fluoro-5-methoxynaphthalen-1-yltrifluoromethanesulfonate

To a solution of 8-fluoro-1-hydroxy-5-methoxy-2-naphthonitrile (200 mg,0.783 mmol) and TEA (0.284 mL, 2.04 mmol) in DCM (5 mL) is addedportionwise at RT N-phenyl-bis(trifluoromethanesulfonimide) (485 mg,1.33 mmol). The RM is stirred overnight at RT, then concentrated underreduced pressure and purified by FC (Hept:DCM 1:0 to 1:1). The titlecompound is obtained as a white solid (275 mg, 100%). LC-MS B:t_(R)=1.10 min; [M+CH₃CN+H]⁺=391.27.

A.1.58.4. 8-Fluoro-1-hydroxy-5-methoxy-2-naphthonitrile

At RT under N2, 8-fluoro-1-hydroxy-5-methoxy-2-naphthaldehyde (453 mg,1.81 mmol) is dissolved in DMF (5 mL), then hydroxylamine hydrochloride(152 mg, 2.16 mmol) is added and the mixture is stirred at RT for 1 h.Acetyl chloride (0.158 mL, 2.19 mmol) is then added and the RM is heatedat 100° C. overnight. After cooling to RT, the mixture is treated with25 mL of water and stirred for 1 h. It is then extracted once with DCMand twice with EtOAc, dried over MgSO₄ and concentrated. The residue ispurified by FC (Hept:EtOAc 1:0 to 1:1) to afford the title compound as abrown solid. LC-MS B: t_(R)=0.89 min; no ionization. ¹H NMR (400 MHz,CDCl₃) δ: 8.85 (m, 1H), 8.17 (dd, J1=2.2 Hz, J2=8.9 Hz, 1H), 7.73 (m,1H), 7.32 (dd, J1=8.7 Hz, J2=10.0 Hz, 1H), 6.97 (dd, J1=3.8 Hz, J2=8.7Hz, 1H), 4.06 (s, 3H).

A.1.58.5. 8-Fluoro-1-hydroxy-5-methoxy-2-naphthaldehyde

To(Z)-8-fluoro-2-(hydroxymethylene)-5-methoxy-3,4-dihydronaphthalen-1(2H)-one(450 mg, 2.03 mmol) in dioxane (10 mL) is added DDQ (506 mg, 2.23 mmol)in one portion. The RM is refluxed for 1 h. After cooling, the mixtureis treated with sat. NaHCO₃ and extracted with EtOAc, dried over MgSO₄and concentrated, to yield the title compound as an orange solid (450mg, 100%). LC-MS B: t_(R)=0.96 min; [M+H]⁺=221.35.

A.1.58.6.(Z)-8-Fluoro-2-(hydroxymethylene)-5-methoxy-3,4-dihydronaphthalen-1(2H)-one

A suspension of NaH (60% in oil, 352 mg, 8.81 mmol) in dry THF (16 mL)under nitrogen is stirred and cooled in an ice-acetone bath, whilstethyl formate (1.22 mL, 14.7 mmol) is added to it. The mixture isstirred below −5° C. for 20 min after which8-fluoro-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-one (500 mg, 2.45mmol) is added in one portion. The RM is allowed to warm to RT. Methanol(1 mL) and then water (1 mL) are added dropwise at 0° C. The mixture istreated with 10 mL of 2N HCl and the THF is partially evaporated underreduced pressure. Then the mixture is extracted with DCM and thecombined extracts are dried (MgSO₄), filtered and evaporated to drynessunder reduced pressure. The residue is purified by FC (Hept:DCM 100:0 to75:25) the desired product as a yellow solid (450 mg, 83%). LC-MS B:t_(R)=0.90 min; [M+H]⁺=223.37.

A.2. Synthesis of boronic acid derivatives of formula (4) A.2.1.3-Ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylicacid

Lithium diisopropylamide (2.0 M in THF/hexanes, 25 mL, 49.6 mmol) isadded dropwise to a solution of 3-ethoxythiophene-2-carboxylic acid(4.00 g, 22.5 mmol) in dry THF (130 mL) at −78° C. The resulting RM isstirred for 30 min at −78° C. then at 0° C. for 10 min. Back at −78° C.,a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.38mL, 45.1 mmol) in dry THF (30 mL) is added dropwise and the RM is slowlyallowed to warm to RT overnight. HCl 2N (50 mL) is added dropwise at 0°C., then the THF is removed in vacuo and the RM is extracted twice withEtOAc. The combined organic layers are washed with brine, dried overMgSO₄ and the solvent is removed. The crude product is purified by FC(Hept/DCM/EtOAc 1:0:0 to 0:9:1), affording the title compound as a whitesolid (5.26 g, 78%). LC-MS A: t_(R)=0.48 min; [M+H]⁺=217.07 (boronicacid, from hydrolysis of the pinacol ester on the LC-MS-column).

A.2.2.5-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-tetrazole

A mixture of2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(500 mg, 1.83 mmol), azidotributyltin(IV) (0.768 mL, 2.75 mmol), and drytoluene (4 mL) is heated at 180° C. for 1 h under MW irradiation. The RMis cooled to RT, treated with HCl 0.1N and extracted with EtOAc. Theorganic layer is dried over MgSO₄ and concentrated under vacuum. Theresidue is purified via FC (Heptane:EtOAc 100:0 to 10:90), affording thetitle compound as a white solid (135 mg, 23%). LC-MS B: t_(R)=0.94 min;[M+H]⁺=317.26.

A.2.2.1.2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A solution of2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(1.50 g, 6.12 mmol), K₂CO₃ (1.69 g, 12.2 mmol) in DMF (4 mL) andiodoethane (0.596 mL, 7.34 mmol) is heated at 120° C. for 30 min. The RMis cooled down to RT, partitioned between DCM and 1N NaHCO₃. The aqueouslayer is re-extracted with DCM, the combined organics are dried (MgSO₄),and concentrated under reduced pressure, affording the title compound asa beige solid (1.31 g, 78%). LC-MS B: t_(R)=1.06 min; [M+CH₃CN]⁺=315.26.

A.2.3.2-(Difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid

To a solution of 4-bromo-2-(difluoromethoxy)benzoic acid (1.00 g, 3.56mmol) in DMF (20 mL) are added at RT bis(pinacolato)diboron (1.355 g,5.34 mmol), KOAc (1.047 g, 10.7 mmol) and1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (11) (208 mg,0.285 mmol). The RM is stirred at 100° C. for 17 h, then cooled to RTand filtered through a pad of celite, washing with EtOAC. The filtrateis washed with water and the aqueous layer is extracted (×2) with EtOAc.Organic layers are combined, washed with brine, dried over MgSO₄,filtered and concentrated under reduced pressure. The residue ispurified by FC eluting with DCM to afford the title compound as anorange solid (846 mg, 76%). LC-MS A: t_(R)=0.37 min; [M+H]⁺=313.11.

Following the procedure described for the synthesis of A.2.3. describedabove, the following boronic acid derivatives are synthesized, startingfrom the corresponding commercially available halides (see table 4).

TABLE 4 Boronic acid derivatives A.2.4.-A.2.6. MS Data t_(R) [min] m/zNo. Compound (LC-MS) [M + H]⁺ A.2.4.2-Cyclobutoxy-5-(4,4,5,5-tetramethyl- 0.91 (A) 319.111,3,2-dioxaborolan-2-yl)benzoic acid A.2.5.1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2- 0.77 (A) 275.27dioxaborolan-2-yl)-1,2-dihydro-3H- indazol-3-one A.2.6.5-(4-(4,4,5,5-Tetramethyl-1,3,2- 0.85 (A) 288.17dioxaborolan-2-yl)phenyl)isoxazol-3-ol

A.2.7.2-Fluoro-6-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid

The title compound is prepared according to the procedure described forA.2.3., starting with 4-bromo-2-fluoro-6-propylbenzoic acid. LC-MS D:t_(R)=0.48 min; [M−H]⁺=307.11.

A.2.7.1. 4-Bromo-2-fluoro-6-propylbenzoic acid

To a solution of 4-bromo-2,6-difluorobenzoic acid (5.00 g, 21.1 mmol) inTHF (50 mL) at 0° C. is added dropwise over 30 min n-propylmagnesiumbromide (2M in THF, 21.6 mL, 43.2 mmol). The RM is allowed to reach RTand stirred for 17 h, then quenched carefully at 0° C. with MeOH (10mL). After stirring for 5 min, the solvent is removed under reducedpressure. The residue is partitioned between EtOAc and 2N HCl. Theaqueous phase is re-extracted with EtOAc (2×). The combined org. phasesare washed with water, brine, dried over MgSO₄, filtered andconcentrated. The residue is purified by FC (heptane/EtOAc 100:0 to70:30) to afford the title compound as a white solid (4.45 g, 81%).LC-MS A: t_(R)=0.84 min; no ionization.

A.2.8.5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)thiophene-2-carboxylicacid

The title compound is prepared according to the procedure described forA.2.1., starting with 3-(trifluoromethyl)thiophene-2-carboxylic acid.LC-MS A: t_(R)=0.59 min; no ionization.

A.2.8.1. 3-(Trifluoromethyl)thiophene-2-carboxylic acid

To a −78° C. solution of 3-(trifluoromethyl)thiophene (0.4 mL, 3.68mmol) in dry THF (10 mL) is added dropwise a solution of butyllithium(1.38M in hexane, 2.93 mL, 4.05 mmol) and the RM is stirred for 30 min.The RM is then poured over an excess of freshly crushed dry ice carbondioxide. Once the RM is back at RT, HCl 1N is added until pH <3 and theRM is extracted with DCM (3×). The organic layer is dried over MgSO₄ andconcentrated under vacuum, affording the title compound as a pale yellowsolid (0.72 g, quantitative). LC-MS A: t_(R)=0.69 min; no ionization.

A.2.9.2-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)aceticacid

A solution of ethyl2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate(1.285 g, 3.82 mmol) in EtOH (15 mL) is treated with NaOH 10% (7.64 mL,19.1 mmol) and the RM is stirred at 50° C. for 30 min. The RM is cooledto RT and diluted with EtOAc. HCl 2N (15 mL) is added to reach acidic pH(<1). The aqueous layer is extracted twice with EtOAc. The resultingorganic phase is dried over MgSO₄ and concentrated, affording the titlecompound as an orange paste. LC-MS A: t_(R)=0.80 min; [M+H]⁺=323.12.

A.2.9.1. Ethyl2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate

A solution of2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.47 g,12.5 mmol) in DMF (50 mL) is treated successively with cesium carbonate(6.10 g, 18.7 mmol) and ethyl bromoacetate (1.48 mL, 13.1 mmol). The RMis stirred at RT for 1 h. Water is added, and the RM is extracted withEt₂O (×3). The combined organic layers are then washed successively withwater (×2) and brine, dried over MgSO₄, filtered, and concentrated underreduced pressure to afford the pure product as a colorless oil (1.46 g,77%). LC-MS A: t_(R)=0.94 min; [M+H]⁺=351.18.

A.2.10.(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)glycine

To a solution of methyl(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)glycinate(207 mg, 0.61 mmol) in THF/H₂O (4:1) (5 mL) is added LiOH.H₂O (51 mg,1.21 mmol) and the RM is stirred at RT for 2 h. The RM is treated withHCl 1N (1 mL) and extracted with EtOAc, dried over MgSO₄ andconcentrated, affording the title compound as a brown oil (0.151 g,78%). LC-MS A: t_(R)=0.82 min; [M+H]⁺=322.07.

A.2.10.1. Methyl(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)glycinate

The title compound is prepared according to the procedure described forA.2.3., starting with methyl (4-bromo-2-ethoxyphenyl)glycinate. LC-MS A:t_(R)=0.93 min; [M+H]⁺=336.28.

A.2.10.2. Methyl (4-bromo-2-ethoxyphenyl)glycinate

To a solution of 4-bromo-2-ethoxyaniline (0.60 g, 2.64 mmol) in DMF (2.5mL) is added DiPEA (0.673 mL, 3.96 mmol) followed by methyl bromoacetate(0.275 mL, 2.9 mmol). The RM is stirred at 90° C. for 1 h in the MWapparatus. The DMF is evaporated under high vacuum and the residue ispurified by FC, eluting with Hept/EtOAc 1:0 to 17:3 affording the titlecompound as a dark red oil (0.71 g, 94%). LC-MS A: t_(R)=0.89 min;[M+H]⁺=288.08.

A.2.11.3-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-oxadiazol-5(4H)-one

The title compound is prepared according to the procedure described forA.2.3., starting with3-(4-bromo-2-ethoxyphenyl)-1,2,4-oxadiazol-5(4H)-one. LC-MS A:t_(R)=0.89 min; [M+H]⁺=333.06.

A.2.11.1. 3-(4-Bromo-2-ethoxyphenyl)-1,2,4-oxadiazol-5(4H)-one

A solution of 4-bromo-2-ethoxy-N′-hydroxybenzimidamide (1.395 g, 5.38mmol), 1,1′-carbonyldiimidazole (1.31 g, 8.08 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (1.23 mL, 8.08 mmol) in dioxane (20mL) is stirred at 90° C. for 4 h 30 min. Once at RT, the productprecipitated upon addition of HCl 1M. Dioxane is partially evaporatedvia N₂ stream prior to filtering off the solid under vacuum, washingwith water. The title compound is obtained as a white solid (1.375 g,90%). LC-MS A: t_(R)=0.81 min, [M+MeCN]⁺=325.89.

A.2.11.2. 4-Bromo-2-ethoxy-N′-hydroxybenzimidamide

A suspension of 4-bromo-2-ethoxybenzonitrile (1.50 g, 6.5 mmol),hydroxylamine hydrochloride (913 mg, 13 mmol) and NaHCO₃ (1.365 g, 16.3mmol) in water (1.32 mL) and EtOH (26.6 mL) is stirred in a sealed tubeat 90° C. for 3 h. Once at RT, the product precipitated from the RM uponaddition of water. The solid is filtered off under high vacuum, washingwith water and some Et₂O. A first crop of pure title compound (947 mg)was thus obtained as white solid. The filtrate is extracted with AcOEt.The organic layer is then washed twice with brine, dried over MgSO₄,filtered and concentrated. The residue is purified by FC (hept/AcOEt5:5) to yield another crop of the pure title compound as a white solid(448 mg), merged with the first batch from precipitation. The titlecompound is obtained as a white solid (1.395 g, 83%). LC-MS A:t_(R)=0.53 min, [M+H]⁺=259.03.

A.2.12.3-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoicacid

The title compound is prepared according to the procedure described forA.2.3., starting with 3-(4-bromo-2-ethoxyphenoxy)propanoic acid. LC-MSD: t_(R)=0.45 min; [M−H]⁺=335.18.

A.2.12.1. 3-(4-Bromo-2-ethoxyphenoxy)propanoic acid

A MW vial is charged with 4-bromo-2-ethoxyphenol (1300 mg, 5.98 mmol),H₂O (5 mL), NaOH 32% (1.332 mL, 14.38 mmol) and 3-chloropropionic acid(674 mg, 6.08 mmol). It is sealed and irradiated at 120° C. The RM isdiluted in water and pH is decreased to pH9 with HCl 2N then isextracted twice with EtOAc. The basic aqueous layer is then acidified topH2 and extracted twice with EtOAc, the combined organic extracts arewashed with water, brine, dried over MgSO₄, filtered and evaporated todryness, yielding the title compound as a white powder (0.448 g, 56%).LC-MS B: t_(R)=0.89 min; [M+H]⁺=289.10.

A.2.13. Methyl(E)-3-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acrylate

The title compound is prepared according to the procedure described forA.2.1., starting with methyl (E)-3-(3-ethoxythiophen-2-yl)acrylate.LC-MS A: t_(R)=1.02 min; [M+H]⁺=339.14.

A.2.13.1. Methyl (E)-3-(3-ethoxythiophen-2-yl)acrylate

A suspension of 3-ethoxythiophene-2-carbaldehyde (2.90 g, 18.6 mmol),methyl bromoacetate (3.07 mL, 33.4 mmol), and triphenylphosphine (7.305g, 27.8 mmol) in aq saturated NaHCO₃ (100 mL) is stirred at RT for 5 h.THF (30 mL) is added and the RM is stirred overnight at RT. It is thenextracted twice with DCM. The combined organic layers are dried overMgSO₄, filtered, and concentrated under vacuum. The crude is purified byFC (Hept/EtOAc 9:1) to afford the title compound as a dark orange oil(2.9 g, 100%). LC-MS A: t_(R)=0.69 min; [M+MeCN]⁺=198.26.

A.2.14.3-(3-Ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)propanoicacid

To a solution of methyl(E)-3-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acrylate[A.2.13.] (250 mg, 0.786 mmol) in MeOH (15 mL) is added Pd/C 5% wet (50mg). Then the vessel is inertized with N₂ and flushed with H₂. The RM isplaced in a autoclave and it is stirred overnight at RT under 4 Bar ofH₂, then for Id at 50° C. under 4 bar of H₂. After filtration on whatmanfilter, NaOH 10% (1.18 mL, 11.8 mmol) is added and the RM is stirred for1 h at RT. It is then treated with HCl 2N until pH <1 and extractedtwice with EtOAc. The organic layer is dried over MgSO₄ andconcentrated, to afford the title compound as a dark yellow oil (287 mg,74%). LC-MS A: t_(R)=0.86 min; [M+H]⁺=327.09.

A.2.15.3-Ethoxy-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobut-3-ene-1,2-dione

3-Ethoxy-4-(tributylstannyl)cyclobut-3-ene-1,2-dione (335 mg, 0.807mmol) and 4-iodophenylboronic acid, pinacol ester (298 mg, 0.904 mmol)are dissolved in DMF (4 mL) with N₂ bubbling for 5 min.Trans-Benzyl(chloro)bis(triphenylphosphine)palladium(II) (36.7 mg,0.0484 mmol) and CuI (15.4 mg, 0.0807 mmol) are added and the RM isstirred at RT for 3 h., then filtered over a microglass filter,concentrated under vacuum and purified by FC (H:EtOAc 100:0 to 80:20) toobtain the title compound as a yellow solid (127 mg, 48%). LC-MS A:t_(R)=0.97 min; [M+MeCN]+=370.07.

A.2.16.3-(3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)oxetan-3-ol

The title compound is prepared according to the procedure described forA.2.1., starting with 3-(3-methoxythiophen-2-yl)oxetan-3-ol. LC-MS A:t_(R)=0.78 min; [M−H2O]+=295.12.

A.2.16.1. 3-(3-Methoxythiophen-2-yl)oxetan-3-ol

To a stirred solution of 3-methoxythiophene (1.00 g, 8.58 mmol) andN,N,N′,N′-tetramethylethylenediamine (1.55 mL, 10.3 mmol) in Et₂O (30mL) is added butyllithium (1.6M in Hexane, 6.4 mL, 10.3 mmol) dropwiseat 0° C. The RM is stirred at RT for 30 min, then 3-oxetanone (0.761 mL,12.9 mmol) is added dropwise and the RM is stirred at RT for 35 min,then diluted with water, the aqueous layer is extracted three times withEtOAc and the combined organic layers are dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue is purified by FC (Heptto Hept/EtOAc 8:2) to give the title compound as a light-yellow oil(1.123 g, 70%). LC-MS A: t_(R)=0.53 min; [M−H₂O]⁺=169.04.

A.2.17. Methyl2-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetate

A suspension of methyl 2-(3-ethoxythiophen-2-yl)acetate (815 mg, 4.07mmol), bis(pinacolato)diboron (633 mg, 2.44 mmol),(1,5-cyclooctadiene)(methoxy)iridium(I) dimer (28.9 mg, 0.0437 mmol) and4,4′-di-tert-butyl-2,2′-dipyridyl (26.8 mg, 0.0999 mmol) in THF (19.3mL) is degassed with a nitrogen stream for 15 min and then stirred at80° C. overnight. The RM is concentrated under reduced pressure and theresidue is purified by FC (Hept to Hept/EtOAc 9:1) to afford the titlecompound as a colourless oil which crystallizes upon standing. LC-MS A:t_(R)=1.03 min; [M+H]⁺=327.14.

A.2.17.1. Methyl 2-(3-ethoxythiophen-2-yl)acetate

Silver benzoate (1800 mg, 7.78 mmol) is added portionwise to a solutionof 2-diazo-1-(3-ethoxythiophen-2-yl)ethan-1-one (2025 mg, 10.3 mmol) andTEA (4.31 mL, 31 mmol) in MeOH (52.7 mL) and the RM is stirred at RT for2 h. It is then diluted with EtOAc and filtered over celite. Thefiltrate is washed twice with sat. aq. NaHCO₃ and once with brine. Theorganic layer is dried over MgSO₄, filtered and concentrated. Theresidue is purified by FC (Hept to Hept/EtOAc 95:5) to yield the titlecompound as a light yellow oil (817 mg, 40%). LC-MS A: t_(R)=0.86 min,[M+H]⁺=201.14.

A.2.17.2. 2-Diazo-1-(3-ethoxythiophen-2-yl)ethan-1-one

A solution of 3-ethoxythiophene-2-carboxylicacid (2500 mg, 14.1 mmol) inDCM (120 mL) is treated with thionyl chloride (1.56 mL, 21.1 mmol),dropwise. The RM is stirred at RT overnight, it is then concentrated invacuo, and the residue is dissolved in MeCN (80 mL). TEA (2.2 mL, 15.8mmol) is added dropwise and the solution is cooled down to 0° C.(Trimethylsilyl)diazomethane (2M solution, 15 mL, 30 mmol) is addeddropwise and the RM is stirred at RT for 2 d. It is then carefullyquenched by dropwise addition of AcOH, until no more bubbling isobserved. The RM is then concentrated and the residue is partitionedbetween EtOAc and water. The organic layer is then washed with sat. aq.NaHCO₃ and with brine, dried (MgSO₄) and concentrated. The residue ispurified by FC (Hept to Hept/EtOAc 8:2) to yield the title compound asan intense yellow solid (2.028 g, 73%). LC-MS A: t_(R)=0.78 min,[M+H]⁺=197.15.

A.2.18. Ethyl2-((2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-2-oxoacetate

The title compound is prepared according to the procedure described forA.2.3., starting with ethyl2-((4-bromo-2-ethoxyphenyl)amino)-2-oxoacetate. LC-MS A: t_(R)=0.98 min;[M+H]⁺=364.21.

A.2.18.1. Ethyl 2-((4-bromo-2-ethoxyphenyl)amino)-2-oxoacetate

To a solution of 4-bromo-2-ethoxyaniline (1.10 g, 4.84 mmol) in DCM (35mL) is added Et₃N (0.748 mL, 5.32 mmol) at RT. The RM is cooled to 0° C.and ethyl oxalyl chloride (0.61 mL, 5.32 mmol) is added dropwise. The RMis stirred for 30 min at 0° C. then allowed to warm to RT and stirredfor 30 min. The RM is partitioned between ethyl acetate and saturatedaqueous solution of NaHCO₃. The two layers are separated and the organiclayers washed with water, brine then dried over MgSO₄, filtered andsolvent removed under vacuo, affording the title compound as a brownsolid (1.52 g, 99%). LC-MS A: t_(R)=0.92 min; [M+MeCN]⁺=316.04.

A.2.19.2-Butoxy-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid

The title compound is prepared according to the procedure described forA.2.3., starting with 4-bromo-2-butoxy-6-fluorobenzoic acid. LC-MS A:t_(R)=0.92 min; [M+H]=339.21.

A.2.19.1. 4-Bromo-2-butoxy-6-fluorobenzoic acid

Methyl 4-bromo-2-butoxy-6-fluorobenzoate (1246 mg, 3.94 mmol) isdissolved in EtOH (15 mL). NaOH 32% (1.82 mL, 19.7 mmol) is added andthe RM is heated up to 60° C. for 1 h. it is then cooled to RT anddiluted with EtOAc. HCl 2N (10 mL) is added to reach acidic pH (<2). Theaq. layer is extracted twice with EtOAc. The resulting organic phase isdried over MgSO₄ and concentrated, affording the title compound as awhite solid. LC-MS D: t_(R)=0.52 min; [M−H]⁺=290.89.

A.2.19.2. Methyl 4-bromo-2-butoxy-6-fluorobenzoate

To a solution of methyl 4-bromo-2-fluoro-6-hydroxybenzoate (1.00 g, 4.02mmol) in DMF (10 mL), is added Cs₂CO₃ (2.62 g, 8.03 mmol) followed by1-iodobutane (0.685 mL, 6.02 mmol). The RM is stirred at 120° C. for 2 hin the MW. The RM is concentrated under reduced pressure, the residue ispartitioned between DCM and water. The aqueous layer is re-extractedwith DCM, the combined organics are dried (MgSO₄), and concentratedunder reduced pressure. Purification by FC (Hept/EtOAc 1:0 to 19:1)affords the title compound as a colourless oil (1.24 g, 99%). LC-MS A:t_(R)=0.98 min; [M+H]⁺=306.84.

A.2.20.2-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)aceticacid

The title compound is prepared according to the procedure described forA.2.3., starting with 2-(4-bromo-2-ethoxyphenyl)acetic acid. LC-MS B:t_(R)=0.91 min; [M+H]⁺=307.27.

A.2.20.1. 2-(4-Bromo-2-ethoxyphenyl)acetic acid

Ethyl 2-(4-bromo-2-ethoxyphenyl)acetate (4538 mg, 16.6 mmol) isdissolved in ethanol (30 mL), then NaOH 10% (27.7 mL, 73.1 mmol) isadded and the RM is stirred overnight at RT. It is then treated bydropwise addition of HCl 37% (6.37 mL, 76.3 mmol), extracted with 60 mLDCM then twice with 30 mL of EtOAc, dried over MgSO₄ and evaporatedunder vacuum, affording the title compound as a pale yellow solid (2.5g, 100%). LC-MS B: t_(R)=0.84 min; [M+H]⁺=258.68.

A.2.20.2. Ethyl 2-(4-bromo-2-ethoxyphenyl)acetate

To 4-bromo-2-hydroxyphenylacetic acid (2800 mg, 11.9 mmol) in DMF (28mL) is added cesium carbonate (7749 mg, 23.8 mmol) and iodoethane (3.35mL, 41.6 mmol). The RM is stirred at RT for 3 h. Water is added and themixture is extracted with Et₂O (3×). The combined organic layers arewashed with water (2×), then dried over MgSO₄ and concentrated todryness. The residue is purified by FC (Hept to Hept/EtOAc 9:1),affording the title compound as a colourless oil (3.02 g, 88%). LC-MS B:t_(R)=1.01 min; [M+H]⁺=287.01.

A.2.21.2-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid

NaOH (2.77N, 16.6 mL, 45.9 mmol) is added to a solution of methyl2-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(7680 mg, 22.9 mmol) in EtOH (30 mL). The RM is stirred overnight at RT,then concentrated under reduced pressure. HCl 25% is added until pH <2and the mixture is extracted twice with DCM. Combined organic layers aredried (MgSO₄), filtered and concentrated under reduced pressure,affording the title compound as a white solid (6.37 g, 94%). LC-MS B:t_(R)=0.89 min; [M+H]⁺=295.18.

A.2.21.1. Methyl2-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

The title compound is prepared according to the procedure described forA.2.3., starting with methyl 4-bromo-2-(methylthio)benzoate. LC-MS B:t_(R)=1.06 min; [M+H]⁺=309.18.

A.2.21.2. Methyl 4-bromo-2-(methylthio)benzoate

To a solution of 4-bromo-2-sulfanylbenzoic acid (5000 mg, 19.5 mmol) inDMF (50 mL) is added portionwise cesium carbonate (13492 mg, 41 mmol),followed by iodomethane (3.07 mL, 48.8 mmol) and the RM is stirred at RTfor 30 min. Water is added and the mixture is extracted with EtOAc (×3).The organic layer is then washed twice with water, dried over MgSO₄ andthe solvent is removed under reduced pressure, affording the titlecompound as an orange oil (5.60 g, quant.). LC-MS B: t_(R)=0.97 min; noionization. ¹H NMR (400 MHz, d6-DMSO) δ: 7.82 (d, J=8.3 Hz, 1H),7.42-7.48 (m, 2H), 3.83 (s, 3H), 2.46 (s, 3H).

B—PREPARATION OF EXAMPLES

Compounds of Examples 1-134 listed in Table 5 below are prepared byapplying either General H or G to the pyrimidine halide derivativesA.1.1.-A.1.45. coupled with commercially available boronic acidderivatives or with boronic acid derivatives A.2.1.-A.2.19.

TABLE 5 Examples 1-134 MS Data t_(R) [min] m/z Ex. Compound (LC-MS) [M +H]⁺ 1 3-Ethoxy-5-{6-[2-(2-methyl-naphthalen-1-yl)-ethylamino]- 1.1 (C)434 pyrimidin-4-yl}-thiophene-2-carboxylic acid 23-Ethoxy-5-{6-[2-(6-methyl-quinolin-5-yl)-ethylamino]- 0.6 (C) 435.1pyrimidin-4-yl}-thiophene-2-carboxylic acid 32-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]- 0.9 (C) 444.1pyrimidin-4-yl}-benzoic acid 43-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]- 1.1 (C) 450.2pyrimidin-4-yl}-thiophene-2-carboxylic acid 52-Cyclobutoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)- 1.0 (C) 470.4ethylamino]-pyrimidin-4-yl}-benzoic acid 62-Ethoxy-4-[6-(2-naphthalen-1-yl-ethylamino)-pyrimidin- 0.9 (C) 414.34-yl]-benzoic acid 74-{6-[2-(2-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin- 1.0 (C) 492.24-yl}-2-ethoxy-benzoic acid 82-Cyclobutoxy-4-[6-(2-naphthalen-1-yl-ethylamino)- 1.0 (C) 440pyrimidin-4-yl]-benzoic acid 93-Ethoxy-5-[6-(2-naphthalen-1-yl-ethylamino)-pyrimidin- 1.1 (C) 420.34-yl]-thiophene-2-carboxylic acid 105-{6-[2-(2-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin- 0.86 (A) 497.87 4-yl}-3-ethoxy-thiophene-2-carboxylic acid 114-{6-[2-(2,3-Dimethyl-naphthalen-1-yl)-ethylamino]- 1.0 (C) 442.3pyrimidin-4-yl}-2-ethoxy-benzoic acid (*1) 125-{6-[2-(2,3-Dimethyl-naphthalen-1-yl)-ethylamino]- 1.2 (C) 448.3pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid (*1) 133-Ethoxy-5-{6-[2-(6-methoxy-2-methyl-quinolin-5-yl)- 0.6 (C) 465ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 145-{6-[2-(2,3-Dimethoxy-naphthalen-1-yl)-ethylamino]- 1.1 (C) 480pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid 155-{6-[2-(7-Chloro-quinolin-8-yl)-ethylamino]-pyrimidin- 1.0 (C) 455.24-yl}-3-ethoxy-thiophene-2-carboxylic acid (*1) 162-Ethoxy-4-{6-[2-(4-methyl-naphthalen-1-yl)-ethylamino]- 1.0(C) 428.3pyrimidin-4-yl}-benzoic acid 172-Cyclobutoxy-4-{6-[2-(4-methyl-naphthalen-1-yl)- 1.1 (C) 454.4ethylamino]-pyrimidin-4-yl}-benzoic acid 183-Ethoxy-5-{6-[2-(4-methyl-naphthalen-1-yl)-ethylamino]- 1.1 (C) 434.1pyrimidin-4-yl}-thiophene-2-carboxylic acid 192-Ethoxy-4-{6-[2-(4-fluoro-naphthalen-1-yl)-ethylamino]- 0.9 (C) 432.1pyrimidin-4-yl}-benzoic acid 202-Cyclobutoxy-4-{6-[2-(4-fluoro-naphthalen-1-yl)- 1.1 (C) 458.3ethylamino]-pyrimidin-4-yl}-benzoic acid 213-Ethoxy-5-{6-[2-(4-fluoro-naphthalen-1-yl)-ethylamino]- 1.1 (C) 438.3pyrimidin-4-yl}-thiophene-2-carboxylic acid 222-Cyclobutoxy-4-[6-(2-quinolin-8-yl-ethylamino)- 0.8 (C) 441.2pyrimidin-4-yl]-benzoic acid (*1) 233-Ethoxy-5-[6-(2-quinolin-8-yl-ethylamino)-pyrimidin- 0.8 (C) 421.44-yl}-thiophene-2-carboxylic acid (*1) 243-Ethoxy-5-{6-[2-(1-methyl-1H-indol-7-yl)-ethylamino]- 1.0 (C) 423pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 253-Ethoxy-5-{6-[2-(1-methyl-1H-indol-4-yl)-ethylamino]- 1.0 (C) 423pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 262-Cyclobutoxy-4-{6-[2-(2-ethoxy-naphthalen-1-yl)- 1.1 (C) 484.1ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 273-Ethoxy-5-{6-[2-(2-ethoxy-naphthalen-1-yl)-ethylamino]- 1.1 (C) 464.2pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 282-Cyclobutoxy-4-{6-[2-(1,2,3-trimethyl-1H-indol-7-yl)- 1.1 (C) 471.1ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 293-Ethoxy-5-{6-[2-(1,2,3-trimethyl-1H-indol-7-yl)- 1.1 (C) 451ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 303-Ethoxy-5-{6-[2-(2-isopropoxy-naphthalen-1-yl)- 1.2 (C) 478.1ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid 313-Ethoxy-5-{6-[2-(2-methyl-benzothiazol-7-yl)- 0.9 (C) 441.1ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid 325-{6-[2-(2-Difluoromethoxy-naphthalen-1-yl)-ethylamino]- 1.1 (C) 486.4pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid (*1) 333-Ethoxy-5-{6-[2-(7-methoxy-quinolin-8-yl)-ethylamino]- 0.7 (C) 451.1pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 343-Ethoxy-5-{6-[2-(5-methoxy-2,3-dihydro-benzofuran- 0.9 (C) 442.14-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2- carboxylic acid (*1) 355-[6-(2-Benzofuran-7-yl-ethylamino)-pyrimidin-4-yl]-3- 1.0 (C) 410.4ethoxy-thiophene-2-carboxylic acid 365-[6-(2-Benzo[1,3]dioxol-4-yl-ethylamino)-pyrimidin-4-yl]- 0.9 (C) 4143-ethoxy-thiophene-2-carboxylic acid 373-Ethoxy-5-{6-[2-(2-methyl-1H-indol-7-yl)-ethylamino]- 1.0 (C) 423.3pyrimidin-4-yl}-thiophene-2-carboxylic acid 383-Ethoxy-5-{6-[2-(2-propoxy-naphthalen-1-yl)-ethylamino]- 0.87 (A) 478.07 pyrimidin-4-yl}-thiophene-2-carboxylic acid 393-Ethoxy-5-{6-[2-(1H-indol-4-yl)-ethylamino]-pyrimidin- 0.9 (C) 409.24-yl}-thiophene-2-carboxylic acid 402-Ethoxy-4-{6-[2-(3-methoxy-naphthalen-1-yl)- 0.9 (C) 444.2ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 412-Cyclobutoxy-4-{6-[2-(3-methoxy-naphthalen-1-yl)- 1.0 (C) 470.3ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 423-Ethoxy-5-{6-[2-(3-methoxy-naphthalen-1-yl)-ethylamino]- 1.1 (C) 450pyrimidin-4-yl}-thiophene-2-carboxylic acid 432-Cyclobutoxy-4-{6-[2-(5-methoxy-benzo[1,3]dioxol-4-yl)- 0.9 (C) 464.2ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 443-Ethoxy-5-{6-[2-(5-methoxy-benzo[1,3]dioxol-4-yl)- 0.9 (C) 444.4ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 453-Ethoxy-5-{6-[2-(5-ethoxy-benzo[1,3]dioxol-4-yl)- 1.0 (C) 458.4ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 463-Ethoxy-5-{6-[2-(1H-indol-7-yl)-ethylamino]-pyrimidin-4- 1.0 (C) 409.4yl}-thiophene-2-carboxylic acid 47(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]- 0.8 (C) 474pyrimidin-4-yl}-phenoxy)-acetic acid (*1) 48(2-Ethoxy-4-{6-[2-(2-methyl-naphthalen-1-yl)-ethylamino]- 0.8 (C) 458.1pyrimidin-4-yl}-phenoxy)-acetic acid (*1) 49(2-Ethoxy-4-{6-[2-(1-methyl-1H-indol-4-yl)-ethylamino]- 0.7 (C) 447.4pyrimidin-4-yl}-phenoxy)-acetic acid (*1) 50(2-Ethoxy-4-{6-[2-(1-methyl-1H-indol-7-yl)-ethylamino]- 0.7 (C) 447.3pyrimidin-4-yl}-phenoxy)-acetic acid (*1) 51{4-[6-(2-Benzofuran-7-yl-ethylamino)-pyrimidin-4-yl]- 0.7 (C) 4342-ethoxy-phenoxyl-acetic acid (*1) 522-Cyclobutoxy-4-{6-[2-(2,5-dimethoxy-naphthalen-1-yl)- 1.0 (C) 500.2ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 535-{6-[2-(2,5-Dimethoxy-naphthalen-1-yl)-ethylamino]- 1.1 (C) 480.3pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid (*1) 544-{6-[2-(2,5-Dimethoxy-naphthalen-1-yl)-ethylamino]- 0.9 (C) 474.1pyrimidin-4-yl}-2-ethoxy-benzoic acid (*1) 55(4-{6-[2-(2,5-Dimethoxy-naphthalen-1-yl)-ethylamino]- 0.8 (C) 504.4pyrimidin-4-yl}-2-ethoxy-phenoxy)-acetic acid (*1) 565-{6-[2-(1,2-Dimethyl-1H-indol-7-yl)-ethylamino]- 1.1 (C) 437.3pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid (*1) 57(4-{6-[2-(1,2-Dimethyl-1H-indol-7-yl)-ethylamino]- 0.8 (C) 461.4pyrimidin-4-yl}-2-ethoxy-phenoxy)-acetic acid (*1) 582-Cyclobutoxy-4-{6-[2-(4-methoxy-naphthalen-1-yl)- 1.0 (C) 470.4ethylamino]-pyrimidin-4-yl}-benzoic acid 593-Ethoxy-5-{6-[2-(4-methoxy-naphthalen-1-yl)- 1.1 (C) 450.3ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid 60(2-Ethoxy-4-{6-[2-(4-methoxy-naphthalen-1-yl)- 0.8 (C) 474.3ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic acid 614-{6-[2-(4-Chloro-naphthalen-1-yl)-ethylamino]-pyrimidin- 1.1 (C) 474.34-yl}-2-cyclobutoxy-benzoic acid 625-{6-[2-(4-Chloro-naphthalen-1-yl)-ethylamino]-pyrimidin- 1.2 (C) 454.24-yl}-3-ethoxy-thiophene-2-carboxylic acid 63(4-{6-[2-(4-Chloro-naphthalen-1-yl)-ethylamino]-pyrimidin- 0.9 (C) 478.44-yl}-2-ethoxy-phenoxy)-acetic acid 642-Cyclobutoxy-4-{6-[2-(6-methoxy-quinolin-5-yl)- 0.7 (C) 471ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 653-Ethoxy-5-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]- 0.6 (C) 451.1pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 66(2-Ethoxy-4-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]- 0.5 (C) 475pyrimidin-4-yl}-phenoxy)-acetic acid (*1) 674-{6-[2-(2-Cyano-naphthalen-1-yl)-ethylamino]-pyrimidin- 0.9 (C) 439.34-yl}-2-ethoxy-benzoic acid (*1) 685-{6-[2-(2-Cyano-naphthalen-1-yl)-ethylamino]-pyrimidin- 1.0 (C) 445.44-yl}-3-ethoxy-thiophene-2-carboxylic acid (*1) 695-{6-[2-(4-Cyano-naphthalen-1-yl)-ethylamino]-pyrimidin- 1.0 (C) 445.34-yl}-3-ethoxy-thiophene-2-carboxylic acid (*1) 705-{6-[2-(2-Difluoromethyl-naphthalen-1-yl)-ethylamino]- 1.1 (C) 470pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid (*1) 714-{6-[2-(4-Difluoromethyl-naphthalen-1-yl)-ethylamino]- 0.9 (C) 464.3pyrimidin-4-yl}-2-ethoxy-benzoic acid (*1) 725-{6-[2-(4-Difluoromethyl-naphthalen-1-yl)-ethylamino]- 1.1 (C) 470.3pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid (*1) 73(4-{6-[2-(4-Difluoromethyl-naphthalen-1-yl)-ethylamino]- 0.8 (C) 494.3pyrimidin-4-yl}-2-ethoxy-phenoxy)-acetic acid (*1) 743-Ethoxy-5-{6-[2-(2-methyl-benzofuran-7-yl)-ethylamino]- 1.0 (C)423.1253 pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 75(2-Ethoxy-4-{6-[2-(2-methyl-benzofuran-7-yl)-ethylamino]- 0.8 (C) 448.3pyrimidin-4-yl}-phenoxy)-acetic acid (*1) 76(2-Ethoxy-4-{6-[2-(4-methyl-naphthalen-1-yl)-ethylamino]- 0.8 (C) 458.3pyrimidin-4-yl}-phenoxy)-acetic acid 77{2-Ethoxy-4-[6-(2-naphthalen-1-yl-ethylamino)-pyrimidin- 0.8 (C) 4444-yl]-phenoxyl-acetic acid 785-{6-[2-(2-Amino-naphthalen-1-yl)-ethylamino]-pyrimidin- 0.9 (C) 435.34-yl}-3-ethoxy-thiophene-2-carboxylic acid 795-{6-[2-(1,5-Dimethyl-1H-indazol-4-yl)-ethylamino]- 0.9 (C) 438pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid 80(4-{6-[2-(1,5-Dimethyl-1H-indazol-4-yl)-ethylamino]- 0.7 (C) 462.3pyrimidin-4-yl}-2-ethoxy-phenoxy)-acetic acid 815-{6-[2-(6-Methoxy-quinolin-5-yl)-ethylamino]-pyrimidin- 0.7 (C) 4754-yl}-3-trifluoromethyl-thiophene-2-carboxylic acid 825-[6-(2-Quinolin-8-yl-ethylamino)-pyrimidin-4-yl]-3- 1.0 (C) 445.4trifluoromethyl-thiophene-2-carboxylic acid (*1) 835-(4-{6-[2-(6-Methoxy-quinolin-5-yl)-ethylamino]- 0.6 (C) 440.4pyrimidin-4-yl}-phenyl)-isoxazol-3-ol [tautomeric form:5-(4-(6-((2-(6-methoxyquinolin-5-yl)ethyl)amino)pyrimidin-4-yl)phenyl)isoxazol-3(2H)-one] 842-Cyclobutoxy-4-{6-[2-(6-methyl-isoquinolin-5-yl)- 0.6 (C) 455ethylamino]-pyrimidin-4-yl}-benzoic acid 853-Ethoxy-5-{6-[2-(6-methyl-isoquinolin-5-yl)-ethylamino]- 0.6 (C) 435.2pyrimidin-4-yl}-thiophene-2-carboxylic acid 86(2-Ethoxy-4-{6-[2-(6-methyl-isoquinolin-5-yl)-ethylamino]- 0.5 (C) 459.2pyrimidin-4-yl}-phenoxy)-acetic acid 872-Cyclobutoxy-4-{6-[2-(7-methoxy-4-methyl-quinolin-8-yl)- 0.7 (C) 485.2ethylamino]-pyrimidin-4-(C)yl}-benzoic acid 88(2-Ethoxy-4-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]- 0.5 (C) 472.1pyrimidin-4-yl}-phenylamino)-acetic acid 893-(3-Methoxy-5-{6-[2-(6-methoxy-quinolin-5-yl)- 0.5 (C) 465.1ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-oxetan-3-ol 902-Ethoxy-4-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]- 0.5 (C) 417pyrimidin-4-yl}-phenol 913-Hydroxy-4-(4-{6-[2-(6-methoxy-quinolin-5-yl)- 0.5 (C) 453ethylamino]-pyrimidin-4-yl}-phenyl)-cyclobut-3-ene- 1,2-dione 923-(4-{6-[2-(1,5-Dimethyl-1H-indazol-4-yl)-ethylamino]- 0.8 (C) 440.3pyrimidin-4-yl}-phenyl)-4-hydroxy-cyclobut-3-ene- 1,2-dione 932-Ethoxy-4-{6-[2-(2-fluoro-naphthalen-1-yl)-ethylamino]- 0.9 (C) 432.3pyrimidin-4-yl}-benzoic acid (*1) 942-Cyclobutoxy-4-{6-[2-(2-fluoro-naphthalen-1-yl)- 1.0 (C) 458ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 953-Ethoxy-5-{6-[2-(2-fluoro-naphthalen-1-yl)-ethylamino]- 1.1 (C) 438.4pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 96(2-Ethoxy-4-{6-[2-(2-fluoro-naphthalen-1-yl)-ethylamino]- 0.8 (C) 462.3pyrimidin-4-yl}-phenoxy)-acetic acid (*1) 97(2-Ethoxy-4-{6-[2-(2-fluoro-naphthalen-1-yl)-ethylamino]- 0.8 (C) 446.3pyrimidin-4-yl}-phenyl)-acetic acid (*1) 981-Ethyl-3-(2-methoxy-4-{6-[2-(6-methoxy-quinolin-5-yl)- 0.5 (C) 473ethylamino]-pyrimidin-4-yl}-phenyl)-urea 99(2-Ethoxy-4-{6-[2-(4-methyl-naphthalen-1-yl)-ethylamino]- 0.9 (C) 442.3pyrimidin-4-yl}-phenyl)-acetic acid 1002-Ethylsulfanyl-4-{6-[2-(4-methyl-naphthalen-1-yl)- 1.0 (C) 444.3ethylamino]-pyrimidin-4-yl}-benzoic acid 1014-[6-(2-Benzo[b]thiophen-7-yl-ethylamino)-pyrimidin- 0.9 (C) 420.24-yl]-2-ethoxy-benzoic acid 1024-[6-(2-Benzo[b]thiophen-7-yl-ethylamino)-pyrimidin- 1.0 (C) 446.34-yl]-2-cyclobutoxy-benzoic acid 1035-[6-(2-Benzo[b]thiophen-7-yl-ethylamino)-pyrimidin- 1.0 (C) 426.24-yl]-3-ethoxy-thiophene-2-carboxylic acid 104{4-[6-(2-Benzo[b]thiophen-7-yl-ethylamino)-pyrimidin- 0.8 (C) 450.34-yl]-2-ethoxy-phenoxyl-acetic acid 105{4-[6-(2-Benzo[b]thiophen-7-yl-ethylamino)-pyrimidin- 0.8 (C) 434.34-yl]-2-ethoxy-phenyl}-acetic acid 1064-[6-(2-Benzo[b]thiophen-4-yl-ethylamino)-pyrimidin- 0.9 (C) 420.34-yl]-2-ethoxy-benzoic acid 1074-[6-(2-Benzo[b]thiophen-4-yl-ethylamino)-pyrimidin- 1.0 (C) 446.34-yl]-2-cyclobutoxy-benzoic acid 1085-[6-(2-Benzo[b]thiophen-4-yl-ethylamino)-pyrimidin- 1.0 (C) 426.24-yl]-3-ethoxy-thiophene-2-carboxylic acid 109{4-[6-(2-Benzo[b]thiophen-4-yl-ethylamino)-pyrimidin- 0.8 (C) 449.94-yl]-2-ethoxy-phenoxyl-acetic acid 110{4-[6-(2-Benzo[b]thiophen-4-yl-ethylamino)-pyrimidin- 0.8 (C) 433.94-yl]-2-ethoxy-phenyl}-acetic acid 1114-{6-[2-(1,5-Dimethyl-1H-indazol-4-yl)-ethylamino]- 0.6 (C) 404pyrimidin-4-yl}-2-ethoxy-phenol 112[2-(6-Methoxy-quinolin-5-yl)-ethyl]-[6-(3,4,5,6- 0.5 (C) 441.2tetrahydro-2H-[1,2′]bipyridinyl-4′-yl)-pyrimidin-4-yl] amine 113{6-[4-(5-Amino-[1,3,4]thiadiazol-2-yl)-phenyl]-pyrimidin- 0.5 (C) 4564-yl}-[2-(6-methoxy-quiolin-5-yl)-ethyl]-amine 114[2-(1,5-Dimethyl-1H-indazol-4-yl)-ethyl]-(6-quinolin- 0.7 (C) 395.16-yl-pyrimidin-4-yl)-amine 115[2-(1,5-Dimethyl-1H-indazol-4-yl)-ethyl]-(6-isoquinolin- 0.7 (C) 395.17-yl-pyrimidin-4-yl)-amine 1163-Hydroxy-4-(4-{6-[2-(2-methoxy-naphthalen-1-yl)- 0.9 (C) 452.1ethylamino]-pyrimidin-4-yl}-phenyl)-cyclobut-3-ene- 1,2-dione 1176-{6-[2-(6-Methoxy-quinolin-5-yl)-ethylamino]-pyrimidin- 0.5 (C) 4274-yl}-1-methyl-1,2-dihydro-indazol-3-one 118(E)-3-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)- 1.2 (C) 476.3ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acrylic acid 1192-Butoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)- 1.1 (C) 472ethylamino]-pyrimidin-4-yl}-benzoic acid 1203-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)- 0.8 (C) 488ethylamino]-pyrimidin-4-yl}-phenoxy)-propionic acid (*1) 1214-{6-[2-(2-Methoxy-naphthalen-1-yl)-ethylamino]- 1.0 (C) 442pyrimidin-4-yl}-2-propyl-benzoic acid 1222-Isobutyl-4-{6-[2-(2-methoxy-naphthalen-1-yl)- 1.0 (C) 456ethylamino]-pyrimidin-4-yl}-benzoic acid 1232-Fluoro-4-{6-[2-(2-methoxy-naphthalen-1-yl)- 1.0 (C) 460ethylamino]-pyrimidin-4-yl}-6-propyl-benzoic acid 1242-Butoxy-6-fluoro-4-{6-[2-(2-methoxy-naphthalen-1-yl)- 1.1 (C) 490.2ethylamino]-pyrimidin-4-yl}-benzoic acid 125{6-[3-Ethoxy-4-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-4-yl}- 0.9 (C) 468.4[2-(2-methoxy-naphthalen-1-yl)-ethyl]amine 1263-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)- 1.0 (C) 484.1ethylamino]-pyrimidin-4-yl}-phenyl)-4H-[1,2,4]oxadiazol- 5-one form:3-(2-ethoxy-4-(6-[(2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-1,2,4-oxadiazol-5-ol] 1272-{6-[2-(2-Methoxy-naphthalen-1-yl)-ethylamino]- 1.0 (C) 439.2pyrimidin-4-yl}-1H-indole-6-carboxylic acid 1282-Difluoromethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)- 1.0 (C) 466.3ethylamino]-pyrimidin-4-yl}-benzoic acid 1292-{6-[2-(2-Methoxy-naphthalen-1-yl)-ethylamino]- 0.9 (C) 439.1pyrimidin-4-yl}-1H-indole-4-carboxylic acid 1302-{6-[2-(2-Methoxy-naphthalen-1-yl)-ethylamino]- 0.9 (C) 439pyrimidin-4-yl}-1H-indole-5-carboxylic acid 1313-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)- 1.0 (C) 478.1ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-propionic acid 132(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)- 1.0 (C) 464.3ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)- acetic acid (*1) 133N-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)- 0.9 (C) 487.3ethylamino]-pyrimidin-4-yl}-phenyl)-oxalamic acid 1345-(4-{6-[2-(2-Methoxy-naphthalen-1-yl)-ethylamino]- 0.9 (C) 439pyrimidin-4-yl}-phenyl)-isoxazol-3-ol [tautomeric form:5-(4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)phenyl)isoxazol-3(2H)-one]

Example 135:3-Ethoxy-5-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)-N-sulfamoylthiophene-2-carboxamide

To a solution of3-ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid (Example 4, 70 mg, 0.156 mmol) in DMSO/THF (2:1, 3 mL) is added CDI(37.9 mg, 0.234 mmol). The RM is heated at 60° C. for 1 h, cooled to RTand treated with sulfamide (33.3 mg, 0.343 mmol) and DBU (0.0582 mL,0.389 mmol). It is then stirred at RT for 2 h, concentrated underreduced pressure, and purified by prep. HPLC, to afford the titlecompound as a beige solid (21 mg, 26%). LC-MS B: t_(R)=0.91 min;[M+H]⁺=528.16.

Example 136:N-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbonyl)-methanesulfonamide

Following the same method as described for example 135, using methylsulfonamide, the title compound is obtained as a beige solid. LC-MS B:t_(R)=0.99 min; [M+H]=527.15.

Example 137:3-(3-Ethoxy-5-{6-[2-(1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(5-(6-((2-(1H-indol-4-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-1,2,4-oxadiazol-5-ol]

To a solution of3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol(61.3 mg, 0.2 mmol) in DMF (2 mL) at RT are added(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(141 mg, 0.31 mmol) and Et₃N (0.14 mL, 1 mmol). The RM is stirred at RTfor 1 h then 2-(1H-indol-4-yl)ethan-1-amine (0.26 mmol) is added. Theresulting RM is stirred overnight at 80° C. The crude RM is purified byprep. HPLC, to afford the title compound as a pale yellow powder (35 mg,35%). LC-MS B: t_(R)=0.85 min; [M+H]⁺=449.02.

a)3-(3-Ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol

A suspension of3-(3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol(5180 mg, 12.1 mmol) in HCl (4M in dioxane, 100 mL) is heated at 100° C.overnight, cooled down to RT, and the solvent is partially removed. Thesolid residue is filtered off washing with water, and dried under highvacuum, affording the title compound as a light yellow solid. LC-MS B:t_(R)=0.66 min; [M+H]⁺=307.01.

b)3-(3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol

To a RM of3-ethoxy-N′-hydroxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboximidamide(6930 mg, 22.6 mmol) and DBU (8.62 mL, 56.5 mmol) in dioxane/DMSO (3:2,220 mL) is added CDI (5498 mg, 33.9 mmol). The RM is stirred at 100° C.for 30 min, then cooled to RT. Evaporation of the solvent andtrituration in 2N HCl afforded the title compound as a yellow solid(7.15 g, 99%). LC-MS A: t_(R)=0.89 min; [M+H]⁺=321.14.

c)3-Ethoxy-N′-hydroxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboximidamide

A suspension of3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carbonitrile (6860 mg,24.7 mmol), TEA (10.3 mL, 74 mmol) and hydroxylamine hydrochloride (2.59mL, 61.7 mmol) in EtOH (220 mL) is refluxed for 3 h, then cooled to RTand treated with water (30 mL) The yellow solid is filtered off anddried under high vacuum. The filtrate is concentrated and the solid istriturated in water, filtered off and combined with the first crop. Thetitle compound is obtained as a yellow solid (6.93 g, 95%). LC-MS B:t_(R)=0.62 min; [M+H]⁺=295.23.

d) 3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carbonitrile

Cyanuric chloride (6248 mg, 33.5 mmol) is added portionwise at 0° C. toa suspension of3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxamide (6940 mg,22.4 mmol) in DMF (130 mL). The RM is then stirred at RT for 45 min. Itis cooled at 0° C. and diluted with water. The solid is filtered off,washing with water and then EtOAc, and dried under high vacuum. Thefiltrate is extracted twice with EtOAc, combined organic layers arewashed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure. Both solids are combined to afford the title compoundas a beige solid (5.49 g, 94%). LC-MS B: t_(R)=1.00 min; [M+H]⁺=262.26.

e) 3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxamide

CDI (4861 mg, 29.1 mmol) is added to a solution of3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylic acid (7410mg, 26.4 mmol) in THF (140 mL) at RT. The RM is stirred for 30 min, thenNH40H (25% solution, 61.1 mL, 397 mmol) is added, and the RM is stirredat RT for 30 min, then concentrated under reduced pressure, and theresidue is triturated in 2N HCl. The title compound is filtered off,dried under high vacuum, and obtained as a yellow solid (6.94 g, 94%).LC-MS B: t_(R)=0.79 min; [M+H]⁺=280.22.

f) 3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylic acid

A suspension of methyl3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylate (7870 mg,26.2 mmol) in MeOH (210 mL) and NaOH 2M (38.8 mL, 419 mmol) is stirredovernight at RT. It is then acidified with HCl 24.5% (8N) (60 mL), MeOHis removed under vacuum and the slurry is filtered, to afford the titlecompound as a yellow solid (7.41 g, 99%). LC-MS B: t_(R)=0.77 min;[M+H]⁺=281.19.

g) Methyl 3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylate

A RM of methyl3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate(10520 mg, 30 mmol), 4-chloro-6-methoxypyrimidine (4645 mg, 31.5 mmol),dichloro(1,1′-bis(diphenylphosphino) ferrocene) palladium (II)dichloromethane adduct) (2449 mg, 3 mmol) and potassium phosphatetribasic monohydrate (20719 mg, 90 mmol) in water (4 mL) and DMF (150mL) is degassed for 20 min under a nitrogen stream, then stirred at RTfor 1 h 15. The RM is filtered through celite, the filtrate isconcentrated under vacuum, the residue is partitioned between water andEtOAc. The organic layer is further washed with brine, dried over MgSO₄,filtered and concentrated. Purification by FC (heptane/EtOAc, from 1:0to 0:1) affords the title compound as a yellow solid (7.87 g, 89%).LC-MS B: t_(R)=0.93 min; [M+H]⁺=295.18.

h) Methyl3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

The title compound is prepared according to the synthesis of A.2.1.using methyl 3-ethoxythiophene-2-carboxylate, and obtained as a whitesolid; LC-MS B: t_(R)=0.63 min; [M+H]⁺=313.13.

Following the procedure described for the synthesis of Example 137, thefollowing examples are synthesized, starting from3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-oland the corresponding commercially available arylethyl amines (see table6).

TABLE 6 Examples 138-144 MS t_(R) [min] Data (LC- m/z Ex. Compound MS C)[M + H]⁺ 1383-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]- 138 1.2pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one form:3-(3-ethoxy-5-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol] 1393-{3-Ethoxy-5-[6-(2-isoquinolin-8-yl-ethylamino)-pyrimidin-4- 139 0.7yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one [tautomeric form:3-(3-ethoxy-5-(6-((2-(isoquinolin-8-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol] 1403-{3-Ethoxy-5-[6-(2-quinolin-8-yl-ethylamino)-pyrimidin-4- 140 0.9yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one [tautomeric form:3-(3-ethoxy-5-(6-((2-(quinolin-8-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol] 1413-(3-Ethoxy-5-{6-[2-(4-methoxy-naphthalen-1-yl)-ethylamino]- 141 1.2pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one form:3-(3-ethoxy-5-(6-((2-(4-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol] 1423-(3-Ethoxy-5-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]- 142 0.7pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one form:3-(3-ethoxy-5-(6-((2-(6-methoxyquinolin-5-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol] 1433-(3-Ethoxy-5-{6-[2-(1H-indol-7-yl)-ethylamino]-pyrimidin-4- 143 1.1yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one form: 3-(5-(6-((2-(1H-indol-7-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-1,2,4-oxadiazol-5-ol] 1443-{3-Ethoxy-5-[6-(2-isoquinolin-5-yl-ethylamino)-pyrimidin-4- 144 0.7yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one [tautomeric form:3-(3-ethoxy-5-(6-((2-(isoquinolin-5-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol]

Example 145:{6-[4-Ethoxy-5-(1H-tetrazol-5-yl)-thiophen-2-yl]-pyrimidin-4-yl}-[2-(6-methoxy-quinolin-5-yl)-ethyl]-amine

Following the procedure described for the synthesis of Example 137,using 2-(6-methoxyquinolin-5-yl)ethan-1-amine hydrochloride and6-(4-ethoxy-5-(1H-tetrazol-5-yl)thiophen-2-yl)pyrimidin-4-ol, the titlecompound is obtained as a pale yellow powder. LC-MS A: t_(R)=0.61 min;[M+H]⁺=475.08.

a) 6-(4-Ethoxy-5-(1H-tetrazol-5-yl)thiophen-2-yl)pyrimidin-4-ol

4-(4-Ethoxy-5-(1H-tetrazol-5-yl)thiophen-2-yl)-6-methoxypyrimidine (30mg, 0.0986 mmol) is treated with HCl 4M in dioxane (0.5 mL) and the RMis stirred at 55-60° C. overnight. It is then concentrated under reducedpressure and purified by prep. HPLC to afford the title compound as awhite solid (12 mg, 42%). LC-MS A: t_(R)=0.59 min; [M+H]⁺=291.04.

b) 4-(4-Ethoxy-5-(1H-tetrazol-5-yl)thiophen-2-yl)-6-methoxypyrimidine

To a solution of3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carbonitrile (Example137-d, 72 mg, 0.276 mmol) in toluene (2.1 mL), trimethylsilylazide(0.0544 mL, 0.413 mmol) and dibutyltin oxide (6.86 mg, 0.0276 mmol) areadded. The RM is stirred at 110° C. overnight in a sealed tube. Thesolvent is evaporated, then the residue is dissolved in MeOH andadjusted to pH=10 with NaOH 2M. The solution is loaded onto a PE_AXcartridge for standard catch&release protocol, which afforded the titlecompound as a yellow solid (43 mg, 51%). LC-MS A: t_(R)=0.78 min;[M+H]⁺=305.06.

Example 146:3-Ethoxy-N-hydroxy-5-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxamidine

Following the procedure described for the synthesis of Example 137-c,using3-ethoxy-5-(6-((2-(6-methoxyquinolin-5-yl)ethyl)amino)pyrimidin-4-yl)thiophene-2-carbonitrile,the title compound is obtained as a yellow solid. LC-MS A: t_(R)=0.56min; [M+H]⁺=465.03.

a)3-Ethoxy-5-(6-((2-(6-methoxyquinolin-5-yl)ethyl)amino)pyrimidin-4-yl)thiophene-2-carbonitrile

Following the procedure described for the synthesis of Example 137,using 2-(6-methoxyquinolin-5-yl)ethan-1-amine hydrochloride and3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophene-2-carbonitrile, the titlecompound is obtained as a beige solid. LC-MS A: t_(R)=0.74 min;[M+H]⁺=432.16.

b) 3-Ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophene-2-carbonitrile

Following the procedure described for the synthesis of Example 137-a,using 3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carbonitrile(Example 137-d), the title compound is obtained as a white solid. LC-MSA: t_(R)=0.69 min; [M+H]⁺=242.12.

Example 147:4-Ethoxy-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylicacid

To a solution of ethyl4-ethoxy-2-(6-hydroxypyrimidin-4-yl)thiazole-5-carboxylate (58.3 mg, 0.2mmol, 1 eq) in DMF (2 mL) are added Et₃N (0.151 mL, 1.08 mmol) and PyBop(150 mg, 0.288 mmol). The RM is stirred at RT for a few minutes untilcomplete dissolution and 2-(2-methoxynaphthalen-1-yl)ethan-1-aminehydrochloride (59 mg, 0.25 mmol) is added. The RM is heated at 100° C.for 30 min in the MW apparatus. NaOH 10% (0.721 mL, 2 mmol) is added andthe RM is stirred at 70° C. overnight. Purification by prep. LC-MSaffords the title compound as a yellow solid. LC-MS B: t_(R)=0.74 min;[M+H]⁺=451.17.

a) Ethyl 4-ethoxy-2-(6-hydroxypyrimidin-4-yl)thiazole-5-carboxylate

Following the procedure described for the synthesis of Example 137-awith ethyl 4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate,the title compound is obtained as a yellow solid. LC-MS B: t_(R)=0.78min; [M+H]⁺=296.15.

b) Ethyl 4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate

To a solution of ethyl4-hydroxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate (1730 mg,6.15 mmol) in DMF (40 mL) at RT under argon is added K₂CO₃ (2168 mg,15.4 mmol), and the RM is heated at 60° C. Iodoethane (0.749 mL, 9.23mmol) is added and the RM is stirred at 75° C. overnight. It is thencooled to RT, and water (75 mL) is added. The aq layer is extracted withDCM, the organic extracts are dried (MgSO₄), filtered and concentratedunder reduced pressure, affording the crude title compound as an orangesolid (1.75 g, 76%). LC-MS B: t_(R)=1.04 min; [M+H]⁺=310.24.

c) Ethyl 4-hydroxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate

To a solution of 6-methoxypyrimidine-4-carbothioamide (1000 mg, 5.85mmol) in toluene (40 mL) is added pyridine (1.9 mL, 23.4 mmol) at RT,followed by diethyl bromomalonate (1.52 mL, 8.19 mmol). The RM is heatedat reflux overnight, then cooled to RT and treated with HCl 2N. Theproduct is filtered off. The layers of the filtrate are separated andthe aq layer is extracted twice with EtOAC. The combined organic layersare dried over MgSO₄, filtered, evaporated to dryness. The residue iscombined with the first crop, yielding the title compound as a brownsolid (1.73 g, 99%). LC-MS B: t_(R)=0.89 min; [M+H]⁺=282.18.

Example 148:4-Ethyl-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylicacid

Following the procedure described for the synthesis of Example 147,using 2-(2-methoxynaphthalen-1-yl)ethan-1-amine hydrochloride and ethyl4-ethyl-2-(6-hydroxypyrimidin-4-yl)thiazole-5-carboxylate, the titlecompound is obtained as a orange solid. LC-MS B: t_(R)=0.96 min;[M+H]⁺=435.03.

a) Ethyl 4-ethyl-2-(6-hydroxypyrimidin-4-yl)thiazole-5-carboxylate

Following the procedure described for the synthesis of Example 137-awith ethyl 4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboxylate, thetitle compound is obtained as a beige solid. LC-MS B: t_(R)=0.73 min;[M+H]⁺=266.26.

b) Ethyl 4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboxylate

To a solution of methyl 2-chloro-3-oxovalerate (0.96 mL, 6.5 mmol) inEtOH (30 mL) is added 6-methoxypyrimidine-4-carbothioamide (1000 mg,5.91 mmol) and the RM is refluxed overnight. Methyl2-chloro-3-oxovalerate (1.31 mL, 8.86 mmol) is added and the RM isfurther refluxed for 24 h, then cooled at RT and treated with water (15mL), cooled down to 0° C. The precipitate is filtered off, rinsed withMeOH and dried under high vacuum, affording the title compound as apinkish solid (485 mg, 28%). LC-MS B: t_(R)=1.07 min; [M+H]⁺=294.20.

Example 149:3-(4-Ethoxy-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(4-ethoxy-2-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)thiazol-5-yl)-1,2,4-oxadiazol-5-ol](*1)

Following the procedure described for the synthesis of Example 137,using 2-(6-methoxyquinolin-5-yl)ethan-1-amine hydrochloride and3-(4-ethoxy-2-(6-hydroxypyrimidin-4-yl)thiazol-5-yl)-1,2,4-oxadiazol-5-ol,the title compound is obtained as a yellow solid. LC-MS B: t_(R)=1.09min; [M+H]⁺=491.09.

a)3-(4-Ethoxy-2-(6-hydroxypyrimidin-4-yl)thiazol-5-yl)-1,2,4-oxadiazol-5-ol

Following the procedure described for the synthesis of Example 137-awith3-(4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazol-5-yl)-1,2,4-oxadiazol-5-ol,the title compound is obtained as a yellowish solid. LC-MS B: t_(R)=0.68min; [M+H]⁺=308.17.

b)3-(4-Ethoxy-2-(6-methoxypyrimidin-4-yl)thiazol-5-yl)-1,2,4-oxadiazol-5-ol

Following the procedure described for the synthesis of Example 137-bwith4-ethoxy-N′-hydroxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboximidamide,the title compound is obtained as a beige solid. LC-MS B: t_(R)=0.94min; [M+H]⁺=321.93.

c)4-Ethoxy-N′-hydroxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboximidamide

Following the procedure described for the synthesis of Example 137-cwith 4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carbonitrile, thetitle compound is obtained as a deep yellow solid. LC-MS B: t_(R)=0.67min; [M+H]⁺=296.17.

d) 4-Ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carbonitrile

NH₄OH (25%, 4.05 mL, 26.3 mmol) and 12 (1824 mg, 7.19 mmol) are added at0° C. to a solution of4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carbaldehyde (465 mg,1.75 mmol) in THF (15 mL) and the RM is stirred at RT for 3 h. It isthen poured in 10 mL of NaHSO₃ 40% (15 mL) and extracted with EtOAc,dried over MgSO₄ and concentrated under vacuum, to afford the titlecompound as an orange solid. LC-MS B: t_(R)=1.02 min; [M+H]⁺=263.25.

e) 4-Ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carbaldehyde

A RM of ethyl 4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate(Example 147-b, 706 mg, 2.64 mmol) in THF (20 mL) is cooled down to −78°C. and DiBAI-H (1M in THF, 5.28 mL, 5.28 mmol) is added dropwise. The RMis stirred at RT overnight. The RM is quenched at 0° C. by dropwiseaddition of water (200 uL), then NaOH 10% (400 uL) and finally water(600 uL). The aluminium precipitate is filtered over a pad of Celite andrinced with EtOAc. The filtrate is dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue is dissolved in DCM (20mL) and MnO₂ (2701 mg, 26.4 mmol) is added. The RM is stirred 5 h at RT,then filtered over a pad of Celite and rinsed with EtOAc. The filtrateis concentrated under reduced pressure, affording the title compound asa light orange solid. LC-MS B: t_(R)=0.97 min; [M+H]⁺=266.25.

Example 150:5-{6-[2-(2-Methoxy-quinolin-8-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylicacid

Following the general procedure F with2-(2-methoxyquinolin-8-yl)ethan-1-amine hydrochloride and5-(6-chloropyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carboxylicacid, the title compound is obtained as a white solid. LC-MS A:t_(R)=0.89 min; [M+H]⁺=475.00.

a) 5-(6-Chloropyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carboxylicacid

Following the general procedure G, using 4,6-dichloropyrimidine and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)thiophene-2-carboxylicacid (A.2.8.), the title compound is obtained as a beige solid. LC-MS B:t_(R)=0.83 min; [M+MeCN]⁺=349.91.

b) 2-(2-Methoxyquinolin-8-yl)ethan-1-amine hydrochloride

Following the general procedure E with tert-butyl(2-(2-methoxyquinolin-8-yl)ethyl)carbamate, the title compound isobtained as a yellow solid. LC-MS A: t_(R)=0.58 min; [M+H]⁺=203.24.

c) Tert-butyl (2-(2-methoxyquinolin-8-yl)ethyl)carbamate

Following the general procedure C with 8-iodo-2-methoxyquinoline, thetitle compound is obtained as a yellow oil. LC-MS A: t_(R)=0.94 min;[M+H]⁺=303.07.

d) 8-Iodo-2-methoxyquinoline

To a suspension of 8-iodo-1,2-dihydroquinolin-2-one (1.55 g, 5.72 mmol)in DMF (0.66 mL, 8.58 mmol) and toluene (10 mL) at 95° C. is addeddropwise POCl₃ (0.425 mL, 4.57 mmol). The RM is stirred at 95° C. for 1h, then cooled to 0° C. and quenched with 32% NaOH (1.59 mL, 17.2 mmol).It is then diluted with 5 mL water and the RM heated up to 30° C. to getthe RM complete dissolved. The layers are separated and the organiclayer is washed with 5 mL water, and concentrated under reducedpressure. The residue is dissolved in 15 mL toluene. NaOMe (25% in MeOH,3.92 mL, 17.2 mmol) is added and the RM is heated up to 80° C. andstirred for 1 h. The RM is cooled down to 10° C., acidified with 32%HCl. The resulting yellow suspension is diluted with 5 ml water, and thesolution is stirred for 10 min, then the layers are separated. Theorganic layer is washed with 5 ml water and evaporated to dryness. Theresidue is purified by FC, eluting with DCM, affording the titlecompound as a light yellow solid (1.36 g, 83%). LC-MS A: t_(R)=0.95 min;[M+H]⁺=286.05.

Example 151:5-{6-[2-(7-Fluoro-2-methoxy-quinolin-8-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylicacid (*1)

Following the general procedure F with2-(7-fluoro-2-methoxyquinolin-8-yl)ethan-1-amine hydrochloride and5-(6-chloropyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carboxylicacid (Example 150-a), the title compound is obtained as a white solid.LC-MS A: t_(R)=0.92 min; [M+H]⁺=492.98.

a) 2-(7-Fluoro-2-methoxyquinolin-8-yl)ethan-1-amine hydrochloride

Following the general procedure E with tert-butyl(2-(7-fluoro-2-methoxyquinolin-8-yl)ethyl)carbamate, the title compoundis obtained as a yellow solid. LC-MS A: t_(R)=0.58 min; [M+H]⁺=221.20.

b) Tert-butyl (2-(7-fluoro-2-methoxyquinolin-8-yl)ethyl)carbamate

Following the general procedure C with8-bromo-7-fluoro-2-methoxyquinoline, the title compound is obtained as awhite solid. LC-MS A: t_(R)=0.96 min; [M+H]⁺=321.06.

Example 152:5-{6-[2-(6-Fluoro-2-methoxy-quinolin-8-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylicacid (*1)

Following the general procedure F with2-(6-fluoro-2-methoxyquinolin-8-yl)ethan-1-amine hydrochloride and5-(6-chloropyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carboxylicacid (Example 150-a), the title compound is obtained as a white solid.LC-MS A: t_(R)=0.91 min; [M+H]⁺=492.98.

a) 2-(6-Fluoro-2-methoxyquinolin-8-yl)ethan-1-amine hydrochloride

Following the general procedure E with tert-butyl(2-(6-fluoro-2-methoxyquinolin-8-yl)ethyl)carbamate, the title compoundis obtained as a yellow solid. LC-MS A: t_(R)=0.60 min; [M+H]⁺=221.18.

b) Tert-butyl (2-(6-fluoro-2-methoxyquinolin-8-yl)ethyl)carbamate

Following the general procedure C with6-fluoro-8-iodo-2-methoxyquinoline, the title compound is obtained as apale yellow solid. LC-MS A: t_(R)=0.97 min; [M+H]⁺=321.09.

c) 6-Fluoro-8-iodo-2-methoxyquinoline

Following the procedure described for Example 150-d, with6-fluoro-8-iodo-1,2-dihydroquinolin-2-one, the title compound isobtained as an off-white solid. LC-MS A: t_(R)=0.97 min; [M+H]⁺=304.16.

Example 153:5-{6-[2-(6-Fluoro-2-methoxy-quinolin-8-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylicacid (*1)

Following the general procedure F with2-(5-fluoro-2-methoxyquinolin-8-yl)ethan-1-amine hydrochloride and5-(6-chloropyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carboxylicacid (Example 150-a), the title compound is obtained as a white solid.LC-MS A: t_(R)=0.91 min; [M+H]⁺=492.98.

a) 2-(5-fluoro-2-methoxyquinolin-8-yl)ethan-1-amine hydrochloride

Following the general procedure E with tert-butyl(2-(6-fluoro-2-methoxyquinolin-8-yl)ethyl)carbamate, the title compoundis obtained as a yellow solid. LC-MS A: t_(R)=0.61 min; [M+H]⁺=221.20.

b) Tert-butyl (2-(6-fluoro-2-methoxyquinolin-8-yl)ethyl)carbamate

Following the general procedure C with6-fluoro-8-iodo-2-methoxyquinoline, the title compound is obtained as ayellow solid. LC-MS A: t_(R)=0.97 min; [M+H]⁺=321.10.

c) 6-Fluoro-8-iodo-2-methoxyquinoline

Following the procedure described for Example 150-d, with5-fluoro-8-iodo-dihydroquinolin-2(1H)-one, the title compound isobtained as a yellow solid. LC-MS A: t_(R)=0.97 min; no ionization.

d) 5-Fluoro-8-iodo-dihydroquinolin-2(1H)-one

A solution of N-(5-fluoro-2-iodophenyl)-3,3-dimethoxypropanamide (24 g,68 mmol) in DCM (20 mL) is added dropwise at RT to sulfuric acid (100 g,1.02 mol). The RM is stirred at RT for 2 h, then concentrated underreduced pressure. The residue is added to 250 g ice, DCM (500 mL) isadded and the RM is stirred for 15 min. The organic layer is separatedand washed with water then concentrated under reduced pressure,affording the title compound as a beige solid (19 g, 97%). LC-MS A:t_(R)=0.72 min; [M+H]⁺=289.97.

e) N-(5-Fluoro-2-iodophenyl)-3,3-dimethoxypropanamide

To a solution of 5-fluoro-2-iodoaniline (15 g, 61.4 mmol) and methyl3,3-dimethoxypropionate (11.5 g, 73.7 mmol) in THF (300 mL) at 0° C. isadded NaHMDS (46 mL, 91.9 mmol) via dropping funnel. The RM is thenstirred at RT for 1.5 h. 40% Citric acid is added to pH=4, the organicsolvent is evaporated under reduced pressure, the residue is dilutedwith water and extracted with DCM. The organic layer is concentrated invacuo, yielding the title compound as a beige solid (24.8 g,quantitative). LC-MS A: t_(R)=0.79 min; [M+H]⁺=353.95.

Example 154:5-{6-[2-(6-Methoxy-1-methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylicacid

Following the general procedure F with2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)ethan-1-amine and5-(6-chloropyrimidin-4-yl)-3-(trifluoromethyl)thiophene-2-carboxylicacid (Example 150-a), the title compound is obtained as an off-whitesolid. LC-MS A: t_(R)=0.66 min; [M+H]⁺=493.01.

a) 2-(6-Methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)ethan-1-amine

Following the general procedure E with tert-butyl(2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)ethyl)carbamate,the title compound is obtained as a beige solid. LC-MS A: t_(R)=0.31min; [M+H]⁺=221.26.

b) Tert-butyl(2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)ethyl)carbamate

To a solution of tert-butyl(2-(6-methoxy-1-methyl-quinolin-5-yl)ethyl)carbamate hydroiodide (328mg, 0.738 mmol) in MeOH (13 mL) and H₂O (1 mL) at 0° C. is added sodiumborohydride (162 mg, 4.29 mmol) portionwise. The RM is then allowed tostir at RT for 4 h 30. The RM is cooled to 0° C. and sodium borohydride(162 mg, 4.29 mmol) are added. The RM is stirred at RT o/n, thenconcentrated under vacuum. The residue is poured into water andextracted 2× with DCM. The combined extracts are washed with brine thendried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue is purified by FC (hept./EtOAc 8:2) to obtain the title compoundas a yellow oil (66 mg, 28%). LC-MS A: t_(R)=0.64 min; [M+H]⁺=321.14.

c) Tert-butyl (2-(6-methoxy-1-methyl-quinolin-5-yl)ethyl)carbamatehydroiodide

A solution of tert-butyl (2-(6-methoxyquinolin-5-yl)ethyl)carbamate (300mg, 0.992 mmol) in acetone (2.2 mL) is treated with iodomethane (0.144mL, 2.29 mmol) then allowed to stir at RT for 2 days. The yellowprecipitate is then filtered, washed with acetone and dried under highvacuum to afford the target product as a light yellow solid (329 mg,75%). LC-MS A: t_(R)=0.61 min; [M+H]⁺=317.19.

d) Tert-butyl (2-(6-methoxyquinolin-5-yl)ethyl)carbamate

Following the general procedure C with 5-bromo-6-methoxyquinoline, thetitle compound is obtained as a brown solid. LC-MS A: t_(R)=0.65 min;[M+H]⁺=240.07.

Example 155:2-(2-Hydroxy-ethoxy)-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid (*1)

Following the general procedure G with6-chloro-N-(2-(2-methoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine (A.1.6.)and methyl2-(2-hydroxyethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate,the title compound is obtained as a white solid. LC-MS B: t_(R)=0.73min; [M+H]⁺=460.21.

a) Methyl2-(2-hydroxyethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

The title compound is prepared according to the procedure described forA.2.3., starting with methyl 4-bromo-2-(2-hydroxyethoxy)benzoate. LC-MSB: t_(R)=0.89 min; [M+H]⁺=323.26.

b) Methyl 4-bromo-2-(2-hydroxyethoxy)benzoate

NaH (101 mg, 4.2 mmol) is added portionwise to a 0° C. solution ofmethyl 4-bromo-2-hydroxybenzoate (500 mg, 2.1 mmol) in DMF (5 mL). TheRM is stirred for a few minutes at 0° C., then 2-bromoethanol (0.235 mL,3.15 mmol) is added and the RM is stirred at 90° C. for 2 h 45, thencooled to RT. Water is added to the RM and it is extracted twice withEtOAc. The combined organic layers are washed with brine, dried overMgSO₄, filtered and concentrated under reduced pressure. The residue ispurified by FC (heptane/EtOAc, 1:0 to 6:4), affording the title compoundas a colorless oil (358 mg, 62%). LC-MS B: t_(R)=0.77 min;[M+H]⁺=275.14.

Example 156:3-(2-Hydroxy-ethoxy)-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid (*1)

Following the general procedure G with6-chloro-N-(2-(2-methoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine (A.1.6.)and7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-5H-thieno[3,2-e][1,4]dioxepin-5-one,the title compound is obtained as a beige solid. LC-MS B: t_(R)=0.77min; [M+H]⁺=465.91.

a)7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-5H-thieno[3,2-e][1,4]dioxepin-5-one

The title compound is prepared according to the procedure described forA.2.17., starting with 2,3-dihydro-5H-thieno[3,2-e][1,4]dioxepin-5-one.LC-MS B: t_(R)=0.51 min; [M+H]⁺=215.41 (mass from boronic acid frompinacol ester cleavage during LC-MS analysis).

b) 2,3-Dihydro-5H-thieno[3,2-e][1,4]dioxepin-5-one

A MW vial is charged with K₂CO₃ (623 mg, 4.5 mmol), methyl3-hydroxythiophene-2-carboxylate (250 mg, 1.5 mmol) and DMF (5 mL). TheRM is stirred for a few minutes then 2-bromoethanol (0.146 mL, 1.95mmol) is added, the vial is capped and heated at 100° C. for 2 h underMW irradiation. 2-Bromoethanol (0.0319 mL, 0.45 mmol) is added and theRM is stirred at 90° C. overnight, under thermal conditions. Once at RT,water is added and the RM is extracted thrice with EtOAc. The combinedorganic layers are dried over MgSO₄, filtered and concentrated underreduced pressure, affording the crude title compound as a brownish solid(338 mg, quantitative). LC-MS B: t_(R)=0.61 min; [M+H]⁺=170.94.

Example 157:3-(2-Dimethylamino-ethoxy)-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid

To a solution of methyl3-hydroxy-5-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)thiophene-2-carboxylate(29 mg, 0.0666 mmol), Cs₂CO₃ (65.1 mg, 0.2 mmol) and TBAI (5 mg, 0.0133mmol) in DMF (1 mL) is added (2-bromoethyl)dimethylamine (49 mg, 0.2mmol) and the RM is heated at 120° C. overnight. The RM is cooled to RTand treated with NaOH 10% (0.266 mL, 0.666 mmol), and further stirred atRT for 4 h. The RM is filtered, rinced with MeOH and purified by prepHPLC to yield the title compound as a red solid (3 mg, 9%). LC-MS B:t_(R)=0.69 min; [M+H]⁺=493.2.

a) Methyl3-hydroxy-5-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)thiophene-2-carboxylate

Following the general procedure F with6-chloro-N-(2-(2-methoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine (A.1.6.)and methyl3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate,the title compound is obtained as an ochre solid. LC-MS B: t_(R)=0.97min; [M+H]⁺=436.22.

b) Methyl3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

Following the procedure described for the synthesis of A.2.1., usingmethyl 3-hydroxythiophene-2-carboxylate, the title compound is obtainedas a brown solid. LC-MS B: t_(R)=0.56 min; no ionization.

Compounds of Examples 158-187 listed in Table 7 below are prepared byapplying either General H or G to the pyrimidine halide derivativesA.1.1.-A.1.58. coupled with commercially available boronic acidderivatives or with boronic acid derivatives A.2.1.-A.2.21.

TABLE 7 Examples 158-187 MS t_(R) [min] Data (LC-MS m/z Ex. Compound C)[M + H]⁺ 1585-{6-[2-(2-Cyano-8-fluoro-5-methoxy-naphthalen-1-yl)-ethylamino]- 1.087493.1 pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid (*1) 1592-Cyclobutoxy-4-{6-[2-(1-methyl-1H-indol-4-yl)-ethylamino]- 0.912 441pyrimidin-4-yl}-benzoic acid (*1) 160(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]- 0.849 458.4pyrimidin-4-yl}-phenyl)-acetic acid 161(4-{6-[2-(4-Bromo-1-methyl-1H-indol-7-yl)-ethylamino]-pyrimidin- 0.849509.1 4-yl}-2-ethoxy-phenyl)-acetic acid (*1) 162(4-{6-[2-(4-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}- 0.945506 2-ethoxy-phenyl)-acetic acid (*1) 163(2-Ethoxy-4-{6-[2-(5-fluoro-naphthalen-1-yl)-ethylamino]- 0.868 446pyrimidin-4-yl}-phenyl)-acetic acid (*1) 164(2-Ethoxy-4-{6-[2-(5-methyl-naphthalen-1-yl)-ethylamino]- 0.882 442.4pyrimidin-4-yl}-phenyl)-acetic acid (*1) 165(2-Ethoxy-4-{6-[2-(6-fluoro-benzo[b]thiophen-4-yl)-ethylamino]- 0.845452.3 pyrimidin-4-yl}-phenyl)-acetic acid (*1) 166(2-Ethoxy-4-{6-[2-(5-methoxy-benzo[b]thiophen-4-yl)-ethylamino]- 0.83464.3 pyrimidin-4-yl}-phenyl)-acetic acid (*1) 167(2-Ethoxy-4-{6-[2-(5-methoxy-1-methyl-1H-indol-4-yl)- 0.757 461.2ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 1684-{6-[2-(6-Methoxy-1-methyl-1H-indol-7-yl)-ethylamino]- 0.975 449.1pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid (*1) 1694-{6-[2-(4-Bromo-1-methyl-1H-indol-7-yl)-ethylamino]- 0.979 497.1pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid (*1) 1704-{6-[2-(2-Bromo-4-fluoro-naphthalen-1-yl)-ethylamino]- 1.096 512.1pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid (*1) 1714-{6-[2-(4-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}- 1.061493.9 2-methylsulfanyl-benzoic acid (*1) 1724-{6-[2-(5-Fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}- 0.965434 2-methylsulfanyl-benzoic acid (*1) 1734-{6-[2-(5-Methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}- 0.979430.3 2-methylsulfanyl-benzoic acid (*1) 1744-{6-[2-(5-Methoxy-benzo[b]thiophen-4-yl)-ethylamino]- 0.906 452.4pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid (*1) 1754-{6-[2-(5-Methoxy-1-methyl-1H-indol-4-yl)-ethylamino]- 0.825 449.3pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid (*1) 1764-{6-[2-(1,5-Dimethyl-1H-indol-4H)-ethylamino]-pyrimidin- 0.863 433.44-yl}-2-methylsulfanyl-benzoic acid (*1) 1774-{6-[2-(5-Ethoxy-benzo[b]thiophen-4-yl)-ethylamino]- 0.984 466.4pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid (*1) 1784-{6-[2-(3-Fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin- 0.969 434.34-yl}-2-methylsulfanyl-benzoic acid (*1) 1792-Ethoxy-4-{6-[2-(2-ethoxy-naphthalen-1-yl)-ethylamino]- 1.003 456.2pyrimidin-4-yl}-benzoic acid (*1) 1804-{6-[2-(4-Bromo-1-methyl-1H-indol-7-yl)-ethylamino]- 0.975 495.2pyrimidin-4-yl}-2-ethoxy-benzoic acid (*1) 1814-{6-[2-(2-Bromo-4-fluoro-naphthalen-1-yl)-ethylamino]- 1.09 510.4pyrimidin-4-yl}-2-ethoxy-benzoic acid (*1) 1824-{6-[2-(4-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin- 1.052 492.24-yl}-2-ethoxy-benzoic acid (*1) 1832-Ethoxy-4-{6-[2-(5-fluoro-naphthalen-1-yl)-ethylamino]- 0.961 432.3pyrimidin-4-yl}-benzoic acid (*1) 1842-Ethoxy-4-{6-[2-(5-methyl-naphthalen-1-yl)-ethylamino]- 0.971 428pyrimidin-4-yl}-benzoic acid (*1) 1852-Ethoxy-4-{6-[2-(5-methoxy-benzo[b]thiophen-4-yl)- 0.898 450.3ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 1862-Ethoxy-4-{6-[2-(5-methoxy-1-methyl-1H-indol-4-yl)- 0.82 447.4ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 1872-Ethoxy-4-{6-[2-(5-ethoxy-benzo[b]thiophen-4-yl)- 0.975 464.2ethylamino]-pyrimidin-4-yl}-benzoic acid (*1)

Example 188:3-{3-Ethoxy-5-[6-(2-quinolin-5-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-{3-ethoxy-5-[6-(2-quinolin-5-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5-ol]

Following the procedure described for the synthesis of Example 137,using3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol(Example 137-a) and 2-(quinolin-5-yl)ethan-1-aminebis(2,2,2-trifluoroacetate), the title compound is obtained as a beigesolid. LC-MS C: t_(R)=0.742 min; [M+H]⁺=461.2.

a) 2-(Quinolin-5-yl)ethan-1-amine bis(2,2,2-trifluoroacetate)

The title compound is obtained from tert-butyl(2-(quinolin-5-yl)ethyl)carbamate, following the general procedure D.LC-MS D: t_(R)=0.57 min; [M+H]⁺=173.00.

b) Tert-butyl (2-(quinolin-5-yl)ethyl)carbamate

The title compound is obtained from 5-bromoquinoline, following thegeneral procedure C. LC-MS B: t_(R)=0.60 min; [M+H]⁺=273.33.

Example 189:3-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]-oxadiazole-5(4H)-thione[tautomeric form:3-(2-ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazole-5-thiol]

To a solution of(E/Z)-2-ethoxy-N′-hydroxy-4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)benzimidamide(194 mg, 0.424 mmol) in dioxane (2 mL) and DMSO (2 mL) at RT under argonare added 1,1′-thiocarbonyldiimidazole (119 mg, 0.636 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.252 mL, 1.65 mmol). The RM isshaken over night at 90° C. It is then cooled to RT, concentrated undervacuo and purified by prep. LC-MS, affording the title compound as abeige powder (65 mg, 31%). LC-MS C: t_(R)=1.091 min; [M+H]⁺=500.3.

a)(E/Z)-2-Ethoxy-N′-hydroxy-4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)benzimidamide

Following the procedure described for the synthesis of Example 137-c,using2-ethoxy-4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)benzonitrile,the title compound is obtained as a grey powder. LC-MS B: t_(R)=0.60min; [M+H]⁺=458.20.

b)2-Ethoxy-4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)benzonitrile

Following the general procedure G with6-chloro-N-(2-(2-methoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine (A.1.6.)and 4-cyano-3-ethoxyphenylboronic acid, the title compound is obtainedas a grey powder. LC-MS B: t_(R)=0.92 min; [M+H]⁺=424.97.

Example 190:3-(4-Ethyl-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(4-ethyl-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5-ol]

Following the General Procedure I, using3-(4-ethyl-2-(6-hydroxypyrimidin-4-yl)thiazol-5-yl)-1,2,4-oxadiazol-5-oland 2-(2-methoxynaphthalen-1-yl)ethan-1-amine hydrochloride, the titlecompound is obtained as a yellow solid. LC-MS C: t_(R)=0.906 min;[M+H]⁺=475.1.

a)3-(4-Ethyl-2-(6-hydroxypyrimidin-4-yl)thiazol-5-yl)-1,2,4-oxadiazol-5-ol

Following the procedure described for the synthesis of Example 137-awith3-(4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazol-5-yl)-1,2,4-oxadiazol-5-ol,the title compound is obtained as a grey solid. LC-MS B: t_(R)=0.64 min;[M+H]⁺=292.17.

b)3-(4-Ethyl-2-(6-ethoxypyrimidin-4-yl)thiazol-5-yl)-1,2,4-oxadiazol-5-ol

Following the procedure described for the synthesis of Example 137-bwith4-ethyl-N′-hydroxy-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboximidamide,the title compound is obtained as a light orange solid. LC-MS B:t_(R)=0.92 min; [M+H]⁺=320.21.

c)4-Ethyl-N′-hydroxy-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboximidamide

Following the procedure described for the synthesis of Example 137-cwith 4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carbonitrile, thetitle compound is obtained as a light yellow solid. LC-MS B: t_(R)=0.66min; [M+H]⁺=294.21.

d) 4-Ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carbonitrile

Following the procedure described for the synthesis of Example 137-dwith 2-(6-ethoxypyrimidin-4-yl)-4-ethylthiazole-5-carboxamide, the titlecompound is obtained as a beige solid. LC-MS B: t_(R)=1.04 min;[M+H]⁺=261.29.

e) 2-(6-Ethoxypyrimidin-4-yl)-4-ethylthiazole-5-carboxamide

Following the procedure described for the synthesis of Example 137-ewith 2-(6-ethoxypyrimidin-4-yl)-4-ethylthiazole-5-carboxylic acid, thetitle compound is obtained as an orange solid. LC-MS B: t_(R)=0.79 min;[M+H]⁺=279.25.

f) 2-(6-Ethoxypyrimidin-4-yl)-4-ethylthiazole-5-carboxylic acid

An ice-chilled solution of ethyl4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboxylate (1000 mg, 3.09mmol) in THF/MeOH 1:1 (15 mL) is treated with NaOH 10% (5.58 mL, 15.5mmol) and stirred at RT for 20 h. The solvents are removed under reducedpressure, the aqueous phase is extracted once with Et₂O. The aqueousphase is then acidified with 2N HCl and extracted with EtOAc (3×). Thecombined organic extracts are dried over MgSO₄, filtered andconcentrated under reduced pressure, yielding the title compound as agreenish solid (522 mg, 64%). LC-MS B: t_(R)=0.88 min; [M+H]⁺=280.24.

g) Ethyl 4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboxylate

To a solution of methyl 2-chloro-3-oxovalerate (0.96 mL, 6.5 mmol) inEtOH (30 mL) is added 6-methoxypyrimidine-4-carbothioamide (1000 mg,5.91 mmol) and the mixture is refluxed overnight. Methyl2-chloro-3-oxovalerate (1.31 mL, 8.86 mmol) is added and the RM isfurther refluxed for 24 h, then cooled at RT and treated with water (15mL), cooled down to 0° C. The precipitate is filtered off, rinsed withMeOH and dried under high vacuum, affording the title compound as apinkish solid (485 mg, 28%). LC-MS B: t_(R)=1.07 min; [M+H]⁺=294.20.

Example 191:3-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzyl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzyl)-[1,2,4]oxadiazol-5-ol]

Following the procedure described for the synthesis of Example 137-bwith2-(2-ethoxy-4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-N-hydroxyacetimidamide,the title compound is obtained as a white solid. LC-MS C: t_(R)=0.888min; [M+H]⁺=498.1.

a)2-(2-Ethoxy-4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-N-hydroxyacetimidamide

Following the procedure described for the synthesis of Example 137-cwith2-(2-ethoxy-4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)phenyl)acetonitrile,the title compound is obtained as a light yellow solid. LC-MS B:t_(R)=0.66 min; [M+H]⁺=294.21.

b)2-(2-Ethoxy-4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)phenyl)acetonitrile

Following the General Procedure G, with6-chloro-N-(2-(2-methoxynaphthalen-1-yl)ethyl)pyrimidin-4-amine (A.1.6.)and2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile,the title compound is obtained as a white solid. LC-MS B: t_(R)=0.89min; [M+H]⁺=439.37.

c)2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile

The title compound is prepared according to the procedure described forA.2.3., starting with 2-(4-bromo-2-ethoxyphenyl)acetonitrile. LC-MS B:t_(R)=1.05 min; [M+H]⁺=288.4.

d) 2-(4-Bromo-2-ethoxyphenyl)acetonitrile

The title compound is prepared according to the procedure described forExample 137-d, starting with 2-(4-bromo-2-ethoxyphenyl)acetamide. LC-MSB: t_(R)=0.97 min; no ionization. ¹H NMR (400 MHz, d6-DMSO) δ: 7.22-7.42(m, 2H), 6.96-7.21 (m, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.78-3.86 (m, 2H),1.36 (m, 3H).

e) 2-(4-bromo-2-ethoxyphenyl)acetamide

The title compound is prepared according to the procedure described forExample 137-e, starting with 2-(4-bromo-2-ethoxyphenyl)acetic acid.LC-MS B: t_(R)=0.76 min; [M+H]⁺=257.85.

II. Biological Assays

Compounds of the present invention may be further characterized withregard to their general pharmacokinetic and pharmacological propertiesusing conventional assays well known in the art such as angiogenesisassays or tumor growth inhibition assays, or for example relating totheir bioavailability in different species (such as rat or dog); or fortheir properties with regard to drug safety and/or toxicologicalproperties using conventional assays well known in the art, for examplerelating to cytochrome P450 enzyme inhibition and time dependentinhibition, pregnane X receptor (PXR) activation, glutathione binding,or phototoxic behavior.

EMT-6 Mouse Tumor Model

The EMT-6 cell line is established from a transplantable murine mammarycarcinoma that arose in a BALB/cCRGL mouse after implantation of ahyperplastic mammary alveolar nodule (Volence F J, et al, J Surg Oncol.1980, 13(1):39-44), obtained from ATCC (American Type culturecollection, Manassas, Va., USA).

EMT-6 tumour cells are grown as monolayer at 37° C. in a humidifiedatmosphere (5% CO2, 95% air) in RPMI 1640 containing 2 mM L glutaminesupplemented with 10% fetal bovine serum. For experimental use, tumourcells are detached from the culture flask with trypsin. The cells arecounted in a hemocytometer and their viability is assessed by trypanblue exclusion.

Tumours are induced in female BALB/c mice by either subcutaneousinjection of 1×10⁶ EMT-6 cells in 200 μL of RPMI 1640 into the rightflank or by injection of 2.5×10⁵ EMT-6 cells in 50 μL of RPMI1640 intothe mammary fat pad tissue. For the latter injection, female BALB/c miceare anaesthetized with Isoflurane and a 5 mm incision is made in theskin over the lateral thorax to expose the mammary fat pad tissue. Aftertumor cell injection the thoracic surface is gently dabbed with a 95%ethanol-dampened cotton-swab to kill tumor cells that may leak from theinjection site. The skin of mice is closed with 4-0 crinerce sutures.

Animals are monitored daily for behavior and survival and twice weeklyfor body weight and tumor growth. Tumor size is measured with calipersand tumor volume is calculated according to the following formula: Tumorvolume=(width²×length)/2.

When tumors reach between 60 and 100 mm³ (depending on the experiment),treatment with EP2 and/or EP4 antagonists is started and compound isgiven daily for at least 3 weeks.

Tumor weight is measured at the end of the study.

Biological In Vitro Assay

The antagonistic activities of the compounds of formula (I) on the EP2and EP4 receptors are also determined in accordance with the followingexperimental method.

Human tumor cell lines expressing endogenously either EP4 or EP2 areused and cAMP accumulation in cells upon PGE2 stimulation is monitored.SF295 glioblastoma cells express high endogenous EP2 and no EP4, whereasBT549 breast cancer cells, express high endogenous EP4 levels and verylow EP2 levels.

As a detection method for cAMP the HTRF (homogeneous time resolvedfluorescence) Cisbio kit (HTRF cAMP dynamic 2 kit 20′000 tests CisbioCat. #62AM4PEC) was used, which is based on a competitive immunoassayusing a Cryptate-labeled anti-cAMP antibody and d2-labeled cAMP. NativecAMP produced by cells or unlabeled cAMP (for the standard curve)compete with exogenously added d2-labeled cAMP (acceptor) for binding tomonoclonal anti-cAMP-Eu3+Cryptate (donor). A FRET signal (FluorescenceResonance Energy Transfer) is obtained only if the labeled anti-cAMPantibody binds the d2 labelled cAMP, thus the specific signal (i.e.energy transfer) is inversely proportional to the concentration of cAMPin the standard or sample.

hEP2 cAMP Assay:

The SF295 cells (NCI/No. 0503170) are detached from culture dishes witha cell dissociation buffer (Invitrogen, 13151-014), and collected ingrowing medium (GM: RPM11640 (Invitrogen 21875)/10% FCS, 1%Penicilin/streptomycin). Cells are counted washed and resuspended inassay buffer (AB; HBSS, 20 mM HEPES, 0.2% BSA; 2 mM IBMX). 4′000 cellsin 5 μL of AB are seeded per well of a small volume 384 well plate(black with flat bottom, Greiner 784076).

Stock solutions of test compounds are made at a concentration of 10 mMin DMSO, and serially diluted in DMSO to concentrations required forinhibition dose response curves (tested concentration range 30 μM-0.4nM; 30 μM-0.015 nM or 1 μM-0.01 nM).

PGE2 (Cayman 14010, stock solution: 75 μM in DMSO) is used as agonist at75 nM final concentration, corresponding to EC80.

2.5 μL of diluted compounds are transferred into the assay plate. Plateis pre-incubated 45 minutes at room temperature. Subsequently, 2.5 μL ofPGE2 (final conc. 75 nM) are transferred into the assay plate. Plate isincubated 30 minutes at room temperature. Five μL of each donor(anti-cAMP cryptate) and acceptor (cAMP-d2) are added and the plate isincubated another hour at room temperature in the dark and then readusing a BMG LABTECH PHERAstar reader (Excitation: 337 nm, Emission: 620and 665 nm).

The obtained Delta F (fluorescence) values (665 nm/620 nM) are convertedinto % cAMP values using the measurements of the cAMP calibratorprovided in the kit. For each compound concentration the percentage ofcAMP compared to DMSO control value as average ±STDEV (eachconcentration is measured in duplicate) is calculated.

IC₅₀ values and curves are generated with XLfit software (IDBS) usingDose-Response One Site model 203. When compounds were measured multipletimes, mean values are given.

hEP4 cAMP Assay:

The BT549 cells (NCI/No. 0507282) are detached from culture dishes witha cell dissociation buffer (Invitrogen, 13151-014), and collected ingrowing medium (GM: RPMI1640 (Invitrogen 21875)/10% FCS, 1%Penicilin/streptomycin). Cells are counted washed and resuspended inassay buffer (AB; HBSS, 20 mM HEPES, 0.2% BSA; 2 mM IBMX). 4′000 cellsin 5 μL of AB are seeded per well of a small volume 384 well plate(black with flat bottom, Greiner 784076).

Stock solutions of test compounds are made at a concentration of 10 mMin DMSO, and serially diluted in DMSO to concentrations required forinhibition dose response curves (tested concentration range 30 μM-0.4nM; 30 μM-0.015 nM or 1 μM-0.01 nM).

PGE2 (Cayman 14010, stock solution: 6 uM in DMSO) is used as agonist at6 nM final concentration, corresponding to EC80.

2.5 μL of diluted compounds are transferred into the assay plate. Plateis pre-incubated 45 minutes at room temperature. Subsequently, 2.5 μL ofPGE2 (final conc. 6 nM) are transferred into the assay plate. Plate isincubated 30 minutes at room temperature. 5 μL of each donor (anti-cAMPcryptate) and acceptor (cAMP-d2) are added and the plate is incubatedanother hour at room temperature in the dark and then read using a BMGLABTECH PHERAstar reader (Excitation: 337 nm, Emission: 620 and 665 nm).

The obtained Delta F (fluorescence) values (665 nm/620 nM) are convertedinto % cAMP values using the measurements of the cAMP calibratorprovided in the kit. For each compound concentration the percentage ofcAMP compared to DMSO control value as average ±STDEV (eachconcentration is measured in duplicate) is calculated.

IC₅₀ values and curves are generated with XLfit software (IDBS) usingDose-Response One Site model 203. When compounds were measured multipletimes, mean values are given.

The antagonistic activities of the compounds of formula (I) on the EP2and EP4 receptors are also determined in accordance with the followingexperimental method.

The assay is using the PathHunter™ HEK 293 PTGER2 and PTGER4 b-arrestincell lines from DiscoverX. The system is based on the Enzyme FragmentComplementation Technology. Two complementing fragments of theb-galactosidase enzyme are expressed within stably transfected cells.The larger portion of b-gal, termed EA for Enzyme Acceptor, is fused tothe C-terminus of b-arrestin 2. The smaller fragment, termed ProLink™tag, is fused to PTGER2 (EP2) or PTRGER4 (EP4) at the C-terminus. Uponactivation, b-arrestin is recruited which forces the interaction ofProLink and EA, allowing complementation of the two fragments of b-galand the formation of a functional enzyme which is capable of hydrolysingthe substrate and generating a chemiluminescent signal.

hEP2 b-Arrestin Assay:

The HEK 293 PTGER2 b-arrestin cells (DiscoverX 93-021-4C1) are detachedfrom culture dishes with a cell dissociation buffer (Invitrogen,13151-014), and collected in growing medium (GM: DMEM+Glutamax-I(Invitrogen 32430)/10% FCS, 1% Penicilin/streptomycin). 5000 cells perwell of a 384 well plate (white with white bottom Greiner 781080) areseeded in 20 μl per well of GM. Plate is incubated at 37° C., 5% CO2 for24 hours.

Stock solutions of test compounds are made at a concentration of 10 mMin DMSO, and serially diluted in DMSO to concentrations required forinhibition dose response curves (tested concentration range 10 μM-2 nMor 1 μM-0.2 nM).

PGE2 (Cayman 14010, stock solution: 10 mM in DMSO) is used as agonist at5 μM final concentration, corresponding to EC80.

Five microliters of diluted compounds are transferred into the assayplate. Plate is pre-incubated 15 minutes at 37° C. Then five microlitersof PGE2 (final conc. 5 μM) are transferred into the assay plate. Plateis incubated 120 minutes at 37° C.

PathHunter Glo Detection Kit components are thawed and mix according tomanufacturer's instructions: 1 part Galacton Star Substrate with 5 partsEmerald II™ Solution, and 19 parts of PathHunter Cell Assay Buffer,respectively. Twelve μl of reagent are transferred to the assay plateand incubate for 1 hour at room temperature in the dark. Luminescencecounts are read on a BMG Fluostar Optima reader according tomanufacturer's instructions.

For each compound concentration calculate of the percentage of activitycompared to DMSO control value as average ±STDEV. (each concentration ismeasured in duplicate)

IC₅₀ values and curves are generated with XLfit software (IDBS) usingDose-Response One Site model 203. When compounds were measured multipletimes, mean values are given.

hEP4 b-Arrestin Assay:

The HEK 293 PTGER4 b-arrestin cells (DiscoverX 93-030-4C1) are detachedfrom culture dishes with a cell dissociation buffer (Invitrogen,13151-014), and collected in growing medium (GM: DMEM+Glutamax-I(Invitrogen 32430)/10% FCS, 1% Penicilin/streptomycin). 5000 cells perwell of a 384 well plate (white with white bottom Greiner 781080) areseeded in 20 ul per well of GM. Plate is incubated at 37° C., 5% CO2 for24 hours.

Stock solutions of test compounds are made at a concentration of 10 mMin DMSO, and serially diluted in DMSO to concentrations required forinhibition dose response curves (tested concentration range 10 μM-2 nMor 1 μM-0.2 nM).

PGE2 (Cayman 14010, stock solution: 100 μM in DMSO) is used as agonistat 20 nM final concentration, corresponding to EC80.

Five microliters of diluted compounds are transferred into the assayplate. Plate is pre-incubated 15 minutes at 37° C. Then five microlitersof PGE2 (final conc. 20 nM) are transferred into the assay plate. Plateis incubated 120 minutes at 37° C.

PathHunter Glo Detection Kit components are thawed and mix according tomanufacturer's instructions: 1 part Galacton Star Substrate with 5 partsEmerald II™ Solution, and 19 parts of PathHunter Cell Assay Buffer,respectively. Twelve μl of reagent are transferred to the assay plateand incubate for 1 hour at room temperature in the dark. Luminescencecounts are read on a BMG Fluostar Optima reader according tomanufacturer's instructions.

For each compound concentration calculate of the percentage of activitycompared to DMSO control value as average ±STDEV. (each concentration ismeasured in duplicate)

IC₅₀ values and curves are generated with XLfit software (IDBS) usingDose-Response One Site model 203. When compounds were measured multipletimes, mean values are given.

Antagonistic activities (IC₅₀ in nM) in the beta-arrestin and cAMPassays of exemplified compounds are displayed in Table 8:

TABLE 8 hEP2 hEP4 hEP2 b- hEP4 b- cAMP cAMP Ex. arr IC₅₀ arr IC₅₀ IC₅₀IC₅₀ 1 5 177 4 47 2 27 311 47 100 3 17 11 292 4 2 20 2 15 5 25 182 24203 6 85 1690 95 910 7 22 67 909 8 71 133 568 9 11 56 9 14 10 5 22 11261 885 12 27 52 17 17 13 25 225 24 138 14 28 17 77 24 15 27 192 25 17116 143 290 176 268 17 95 281 270 18 19 9 21 7 19 129 93 646 20 73 199680 21 32 77 16 62 22 949 613 23 303 293 248 239 24 17 203 15 96 25 15145 15 48 26 10 392 11 566 27 3 53 2 33 28 1400 684 988 29 241 164 136148 30 115 83 23 61 31 201 1410 190 567 32 10 19 10 72 33 56 252 78 22334 39 114 64 152 35 115 113 76 92 36 262 368 37 126 53 596 38 22 48 3981 386 50 101 40 525 853 41 297 711 42 32 15 31 35 43 252 797 44 36 5137 42 45 10 53 10 44 46 110 311 85 244 47 45 123 654 48 22 147 729 49108 160 458 50 399 631 51 473 853 52 779 758 53 5 305 17 54 878 420 55829 300 56 53 52 292 57 508 962 58 825 401 59 156 17 141 38 60 845 38461 113 183 745 62 32 19 24 29 63 99 239 300 64 106 80 872 65 18 78 15 7566 350 227 714 67 29 499 25 309 68 7 24 3 22 69 78 48 79 66 70 78 163368 71 91 374 128 72 50 8 50 6 73 34 465 102 74 212 117 78 88 75 976 88976 66 259 116 77 418 403 78 41 50 56 51 79 36 196 25 92 80 338 495 81116 427 30 205 82 987 960 83 119 89 428 84 149 179 989 85 30 244 32 13086 177 77 674 87 70 103 850 88 94 155 645 89 178 197 878 90 36 58 351 91146 228 818 92 287 544 93 36 36 427 94 34 53 368 95 8 51 4 21 96 66 180426 97 132 218 355 98 354 335 99 177 765 225 100 133 206 206 76 101 128129 619 102 145 224 263 103 33 314 79 73 104 335 356 105 784 685 106 258867 107 149 250 267 108 31 225 52 31 109 726 452 110 878 597 111 50 171855 112 190 210 685 113 47 27 459 114 224 35 492 115 245 95 493 116 251140 67 241 117 686 564 163 118 11 12 94 55 119 18 222 12 200 120 16 7588 206 121 12 308 5 53 122 62 41 308 123 31 29 550 124 35 100 446 125 829 24 29 126 5 34 20 43 127 9 20 416 128 10 291 3 250 129 87 15 289 13013 27 546 131 54 88 73 157 132 61 49 381 133 6 41 22 79 134 8 280 91 351135 5 23 3 67 136 3 24 10 86 137 16 37 37 37 138 3 4 6 8 139 186 48 52628 140 119 15 142 17 141 61 4 72 17 142 7 10 40 27 143 31 21 90 105 14430 20 71 40 145 16 18 81 53 146 66 119 405 147 7 40 10 44 148 20 264 27548 149 5 6 15 52 150 524 321 151 414 478 214 228 152 107 506 197 153438 283 154 57 125 144 177 155 45 2230 16 296 156 7 51 157 43 1910 1431040 158 126 3 286 3 159 44 864 110 1050 160 24 667 79 252 161 628 363162 219 114 163 80 294 202 180 164 44 181 130 110 165 864 555 166 51 216167 69 758 168 93 108 169 230 350 170 474 407 171 68 149 88 130 172 45605 173 10 175 15 140 174 8 298 175 3 245 176 3 550 177 4 334 178 142871 179 4 934 8 1500 180 441 235 181 962 887 182 142 193 209 182 183 60701 184 27 375 48 330 185 14 200 186 9 500 187 10 563 188 59 282 324 22189 5 16 190 13 34 8 1250 191 23 219

1. A method of treatment of a cancer wherein said cancer is treated bymodulating an immune response comprising a reactivation of the immunesystem in the tumor; comprising administering to a subject in needthereof an effective amount of a compound of formula (I)

or of a pharmaceutically acceptable salt thereof; and optionallyadministering one or more chemotherapy agents and/or radiotherapy and/ortargeted therapy; wherein in the compounds of the formula (I) ring (A)in the fragment:

represents an aromatic 5- or 6-membered ring or a non-aromatic 5- or6-membered ring, which ring (A) is fused to the phenyl group, whereinindependently said ring (A) optionally contains one or two heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein saidfragment is optionally substituted with (R¹)_(n); wherein (R¹)_(n)represents one, two, three, or four optional substituents, wherein saidsubstituents R¹ are independently selected from (C₁₋₃)alkyl,(C₂₋₃)alkenyl, (C₂₋₃)alkynyl, (C₁₋₃)alkoxy, halogen, —S—(C₁₋₃)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, cyano, oxo, or amino; R³represents hydrogen, methyl or trifluoromethyl; R^(4a) and R^(4b)independently represent hydrogen, methyl, or R^(4a) and R^(4b) togetherwith the carbon atom to which they are attached represent acycloprop-1,1-diyl group; R^(5s) and R^(5b) independently representhydrogen, methyl, or R^(5a) and R^(5b) together with the carbon atom towhich they are attached represent a cycloprop-1,1-diyl group; Ar¹represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenylor 5- or 6-membered heteroaryl independently is mono-, di- ortri-substituted, wherein the substituents are independently selectedfrom (C₁₋₆)alkyl; (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl, wherein said(C₁₋₃)fluoroalkyl is optionally substituted with hydroxy;(C₁₋₃)fluoroalkoxy; halogen; cyano; (C₃₋₆)cycloalkyl, wherein said(C₃₋₆)cycloalkyl is unsubstituted or mono-substituted with amino;(C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein said(C₄₋₆)cycloalkyl containing a ring oxygen atom is unsubstituted ormono-substituted with hydroxy; (C₃₋₆)cycloalkyl-oxy; hydroxy;—X¹—CO—R^(O1), wherein X¹ represents a direct bond, (C₁₋₃)alkylene,—O—(C₁₋₃)alkylene-*, —NH—(C₁₋₃)alkylene-*, —S—CH₂—*, —CF₂—, —CH═CH—,—CH≡CH—, —NH—CO—*, —CO—, or (C₃₋₅)cycloalkylene; wherein the asterisksindicate the bond that is linked to the —CO—R^(O1) group; and R^(O1)represents —OH; —O—(C₁₋₄)alkyl; —NH—SO₂—R^(S3) wherein R^(S3) represents(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl optionallycontains a ring oxygen atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the(C₃₋₆)cycloalkyl optionally contains a ring oxygen atom,(C₁₋₃)fluoroalkyl, or —NH₂; —O—CH₂—CO—R^(O4), wherein R^(O4) representshydroxy, or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]2; —O—CH₂—O—CO—R^(O5),wherein R^(O5) represents (C₁₋₄)alkyl or (C₁₋₄)alkoxy;—O—CH₂—CH₂—N[(C₁₋₄)alkyl]2; or(5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-; —CO—CH₂—OH;

2-hydroxy-3,4-dioxo-cyclobut-1-enyl; hydroxy-(C₁₋₄)alkyl;dihydroxy-(C₂₋₄)alkyl; hydroxy-(C₂₋₄)alkoxy; (C₁₋₄)alkoxy-(C₂₋₄)alkoxy;—(CH₂)_(r)—CO—NR^(N3)R^(N4) wherein r represents the integer 0 or 1; andwherein R^(N3) and R^(N4) independently represent hydrogen, (C₁₋₄)alkyl,hydroxy-(C₂₋₄)alkyl, (C₁₋₃)alkoxy-(C₂₋₄)alkyl, or hydroxy;—X²—NR^(NM)R^(N2), wherein X² represents —(CH₂)_(m)—, wherein mrepresents the integer 0 or 1; or X² represents —O—CH₂—CH₂—*, whereinthe asterisk indicates the bond that is linked to the —NR^(N1)R^(N2)group; and wherein R^(N1) and R^(N2) independently represent hydrogen,(C₁₋₄)alkyl, (C₁₋₄)alkoxy-(C₂₋₄)alkyl, (C₃₋₆)cycloalkyl, or(C₂₋₃)fluoroalkyl; or R^(N1) independently represents hydrogen or(C₁₋₄)alkyl, and R^(N2) independently represents —CO—H, —CO—(C₁₋₃)alkyl,—CO—(C₁₋₃)alkylene-OH, or —CO—O—(C₁₋₃)alkyl; or R^(N1) and R^(N2)together with the nitrogen to which they are attached form a 4-, 5- or6-membered saturated ring optionally containing one ring oxygen or ringsulfur atom, wherein said ring is unsubstituted, or mono-substitutedwith oxo on a ring carbon atom, or disubstituted with oxo on a ringsulfur atom; —NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6)independently represent hydrogen or (C₁₋₄)alkyl; —SO₂—R^(s1) whereinR^(S1) represents hydroxy, (C₁₋₄)alkyl, or —NR^(N7)R^(N8) wherein R^(N7)and R^(N8) independently represent hydrogen or (C₁₋₃)alkyl; —S—R²wherein R^(S2) represents (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl optionallycontaining one ring oxygen atom; —(CH₂)_(q)-HET¹, wherein q representsthe integer 0, 1 or 2; and wherein HET¹ represents5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl,3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl, or5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; —(CH₂)_(p)-HET, wherein prepresents the integer 0 or 1; and wherein HET represents a 5- or6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl isunsubstituted, or mono- or di-substituted, wherein the substituents areindependently selected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, —COOH, hydroxy,hydroxy-(C₁₋₃)alkyl, (C₃-5)cycloalkyl optionally containing one ringoxygen atom, or —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independentlyrepresent hydrogen, (C₁₋₃)alkyl, or hydroxy-(C₂₋₄)alkyl; or Ar¹represents 8- to 10-membered bicyclic heteroaryl; wherein said 8- to10-membered bicyclic heteroaryl independently is unsubstituted, mono-,or di-substituted, wherein the substituents are independently selectedfrom (C₁₋₄)alkyl; (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy;halogen; cyano; hydroxy, or —(C₀₋₃)alkylene-COOR^(O2) wherein R^(O2)represents hydrogen or (C₁₋₄)alkyl; or Ar¹ represents a group of thestructure (Ar-III):

wherein ring (B) represents a non-aromatic 5- or 6-membered ring fusedto the phenyl group, wherein ring (B) comprises one or two heteroatomsindependently selected from nitrogen and oxygen; wherein said ring (B)independently is unsubstituted, mono-, or di-substituted, wherein thesubstituents are independently selected from oxo, (C₁₋₆)alkyl and—(C₀₋₃)alkylene-COOR^(O3) wherein R^(O3) represents hydrogen or(C₁₋₃)alkyl.
 2. A method according to claim 1, wherein said compound offormula (I) is a compound of formula (II)

wherein ring (A) in the fragment:

represents an aromatic 5- or 6-membered ring or a non-aromatic 5- or6-membered ring, which ring (A) is fused to the phenyl group, whereinindependently said ring (A) optionally contains one or two heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein saidfragment is optionally substituted with (R¹)_(n); wherein (R¹)_(n)represents one, two, three, or four optional substituents, wherein saidsubstituents R¹ are independently selected from (C₁₋₃)alkyl,(C₂₋₃)alkenyl, (C₂₋₃)alkynyl, (C₁₋₃)alkoxy, halogen, —S—(C₁₋₃)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, cyano, oxo, or amino; R³represents hydrogen, or methyl; and Ar¹ represents a phenyl group of thestructure (Ar-I):

wherein R^(p) represents (C₄₋₆)cycloalkyl containing a ring oxygen atom,wherein said (C₄₋₆)cycloalkyl containing a ring oxygen atom isunsubstituted or mono-substituted with hydroxy; hydroxy; —X¹—CO—R^(O1),wherein X¹ represents a direct bond, (C₁₋₃)alkylene,—O—(C₁₋₃)alkylene-*, —NH—(C₁₋₃)alkylene-*, —S—CH₂—*, —CF₂—, —CH═CH—,—CH≡CH—, —NH—CO—*, —CO—, or (C₃₋₅)cycloalkylene; wherein the asterisksindicate the bond that is linked to the —CO—R^(O1) group; and R^(O1)represents —OH; —O—(C₁₋₄)alkyl; —NH—SO₂—R^(S3) wherein R^(S3) represents(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl optionallycontains a ring oxygen atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the(C₃₋₆)cycloalkyl optionally contains a ring oxygen atom,(C₁₋₃)fluoroalkyl, or —NH₂; —O—CH₂—CO—R^(O4), wherein R^(O4) representshydroxy, or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]2; —O—CH₂—O—CO—R^(O5),wherein R^(O5) represents (C₁₋₄)alkyl or (C₁₋₄)alkoxy;—O—CH₂—CH₂—N[(C₁₋₄)alkyl]2; or(5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;

2-hydroxy-3,4-dioxo-cyclobut-1-enyl; hydroxy-(C₂₋₄)alkoxy;—(CH₂)_(r)—CO—NR^(N3)R^(N4) wherein r represents the integer 0 or 1; andwherein R^(N3) and R^(N4) independently represent hydrogen, (C₁₋₄)alkyl,hydroxy-(C₂₋₄)alkyl, (C₁₋₃)alkoxy-(C₂₋₄)alkyl, or hydroxy;—NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6) independently representhydrogen or (C₁₋₄)alkyl; —(CH₂)_(q)-HET¹, wherein q represents theinteger 0, 1 or 2; and wherein HET¹ represents5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl,3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl, or5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; —(CH₂)_(p)-HET, wherein prepresents the integer 0 or 1; and wherein HET represents a 5-memberedheteroaryl, wherein said 5-membered heteroaryl is unsubstituted, ormono- or di-substituted, wherein the substituents are independentlyselected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, —COOH, hydroxy,hydroxy-(C₁₋₃)alkyl, (C₃₋₅)cycloalkyl optionally containing one ringoxygen atom, or —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independentlyrepresent hydrogen, (C₁₋₃)alkyl, or hydroxy-(C₂₋₄)alkyl; R^(m1)represents hydrogen; (C₁₋₆)alkyl; (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl;(C₁₋₃)fluoroalkoxy; halogen; (C₃₋₆)cycloalkyl; (C₃₋₆)cycloalkyl-oxy;hydroxy; hydroxy-(C₂₋₄)alkoxy; —X²—NR^(N1)R^(N2), wherein X² representsa direct bond; or X² represents —O—CH₂—CH₂—*, wherein the asteriskindicates the bond that is linked to the —NR^(N1)R^(N2) group; andwherein R^(N1) and R^(N2) independently represent hydrogen, (C₁₋₄)alkyl,or (C₃₋₆)cycloalkyl; —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl,(C₃₋₆)cycloalkyl optionally containing one ring oxygen atom; R^(m2)represents hydrogen, methyl, fluoro, or chloro; and R^(o1) representshydrogen; or, in case R^(m2) represents hydrogen, R^(o1) representshydrogen or fluoro; or Ar¹ represents a 5-membered heteroaryl group ofthe structure (Ar-II):

wherein Y represents CR⁸ wherein R⁸ represents hydrogen or halogen; or Yrepresents N; R⁷ represents (C₄₋₆)cycloalkyl containing a ring oxygenatom, wherein said (C₄₋₆)cycloalkyl containing a ring oxygen atom isunsubstituted or mono-substituted with hydroxy; —X¹—CO—R^(O1), whereinX¹ represents a direct bond, (C₁₋₃)alkylene, —O—(C₁₋₃)alkylene-*,—NH—(C₁₋₃)alkylene-*, —S—CH₂—*, —CF₂—, —CH═CH—, —CH≡CH—, —NH—CO—*, —CO—,or (C₃₋₅)cycloalkylene; wherein the asterisks indicate the bond that islinked to the —CO—R^(O1) group; and R^(O1) represents —OH;—O—(C₁₋₄)alkyl; —NH—SO₂—R^(S3) wherein R^(S3) represents (C₁₋₄)alkyl,(C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl optionally contains a ringoxygen atom, (C₃-6)cycloalkyl-(C₁₋₃)alkylene wherein the(C₃₋₆)cycloalkyl optionally contains a ring oxygen atom,(C₁₋₃)fluoroalkyl, or —NH₂; —O—CH₂—CO—R^(O4), wherein R^(O4) representshydroxy, or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]2; —O—CH₂—O—CO—R^(O5),wherein R^(O5) represents (C₁₋₄)alkyl or (C₁₋₄)alkoxy;—O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂; or(5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;

2-hydroxy-3,4-dioxo-cyclobut-1-enyl; hydroxy-(C₂₋₄)alkoxy;—(CH₂)_(r)—CO—NR^(N3)R^(N4) wherein r represents the integer 0 or 1; andwherein R^(N3) and R^(N4) independently represent hydrogen, (C₁₋₄)alkyl,hydroxy-(C₂₋₄)alkyl, (C₁₋₃)alkoxy-(C₂₋₄)alkyl, or hydroxy;—NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6) independently representhydrogen or (C₁₋₄)alkyl; —(CH₂)_(q)-HET¹, wherein q represents theinteger 0, 1 or 2; and wherein HET¹ represents5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl,3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl, or5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; —(CH₂)_(p)-HET, wherein prepresents the integer 0 or 1; and wherein HET represents a 5-memberedheteroaryl, wherein said 5-membered heteroaryl is unsubstituted, ormono- or di-substituted, wherein the substituents are independentlyselected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, —COOH, hydroxy,hydroxy-(C₁₋₃)alkyl, (C₃₋₅)cycloalkyl optionally containing one ringoxygen atom, or —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independentlyrepresent hydrogen, (C₁₋₃)alkyl, or hydroxy-(C₂₋₄)alkyl; R⁶ represents(C₁₋₆)alkyl; (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy;halogen; hydroxy; (C₃₋₆)cycloalkyl; (C₃₋₆)cycloalkyl-oxy;hydroxy-(C₂₋₄)alkoxy; —X²—NR^(N1)R^(N2), wherein X² represents a directbond; or X² represents —O—CH₂—CH₂—*, wherein the asterisk indicates thebond that is linked to the —NR^(N1)R^(N2) group; and wherein R^(N1) andR^(N2) independently represent hydrogen, (C₁₋₄)alkyl, or(C₃₋₆)cycloalkyl; —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl,(C₃₋₆)cycloalkyl optionally containing one ring oxygen atom; or Ar¹represents 8- to 10-membered bicyclic heteroaryl; wherein said 8- to10-membered bicyclic heteroaryl independently is mono-substituted with—(C₀₋₃)alkylene-COOR^(O2) wherein R^(O2) represents hydrogen or(C₁₋₄)alkyl; or Ar¹ represents a group of the structure (Ar-III):

which is selected from 2-oxo-2,3-dihydro-benzooxazol-6-yl,3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, and1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl; or a pharmaceuticallyacceptable salt thereof.
 3. A method according to claim 2; wherein Ar¹represents a group selected from:

or a pharmaceutically acceptable salt thereof.
 4. A method according toclaim 3; wherein in the fragment

ring (A) represents an aromatic 5- or 6-membered ring fused to thephenyl group, wherein said ring (A) optionally contains one or twoheteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein said fragment is optionally substituted with (R¹)_(n); wherein(R¹)_(n) represents one, two, three, or four optional substituents,wherein said substituents R¹ are independently selected from(C₁₋₃)alkyl, (C₁₋₃)alkoxy, halogen, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, cyano, or amino; or ring (A) represents anon-aromatic 5- or 6-membered ring fused to the phenyl group, whereinsaid ring (A) optionally contains one or two heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; wherein said fragment isoptionally substituted with (R¹)_(n); wherein (R¹)_(n) represents one,two, or three optional substituents, wherein said substituents R¹ areindependently selected from (C₁₋₃)alkyl, (C₁₋₃)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, or oxo; or a pharmaceuticallyacceptable salt thereof.
 5. A compound of formula (III)

wherein in compounds of the formula (III), ring (A) in the fragment:

represents an aromatic 5- or 6-membered ring or a non-aromatic 5- or6-membered ring, which ring (A) is fused to the phenyl group, whereinindependently said ring (A) optionally contains one or two heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein saidfragment is optionally substituted with (R¹)_(n); wherein (R)_(n)represents one, two, three, or four optional substituents, wherein saidsubstituents R¹ are independently selected from (C₁₋₃)alkyl,(C₂₋₃)alkenyl, (C₂₋₃)alkynyl, (C₁₋₃)alkoxy, halogen, —S—(C₁₋₃)alkyl,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, cyano, oxo, or amino; and Ar¹represents a phenyl group of the structure (Ar-I):

wherein R^(p) represents —X¹—CO—R^(O1), wherein X¹ represents a directbond, (C₁₋₃)alkylene, —O—(C₁₋₃)alkylene-*, —NH—(C₁₋₃)alkylene-*,—CH═CH—, —NH—CO—*, or (C₃₋₅)cycloalkylene; wherein the asterisksindicate the bond that is linked to the —CO—R^(O1) group; and R^(O1)represents —OH; —O—(C₁₋₄)alkyl; —NH—SO₂—R^(S3) wherein R^(S3) represents(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl optionallycontains a ring oxygen atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the(C₃₋₆)cycloalkyl optionally contains a ring oxygen atom,(C₁₋₃)fluoroalkyl, or —NH₂; HET¹, wherein HET¹ represents5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl, or3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl; or HET, wherein HET representsa group selected from 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl,2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl,2-amino-oxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl,5-methylamino-[1,3,4]thiadiazol-2-yl, 5-amino-[1,2,4]oxadiazol-3-yl;R^(m1) represents (C₁₋₆)alkyl; (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl;(C₁₋₃)fluoroalkoxy; halogen; (C₃₋₆)cycloalkyl; (C₃₋₆)cycloalkyl-oxy;hydroxy-(C₂₋₄)alkoxy; or —S—R^(S2) wherein R^(S2) represents(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl optionally containing one ring oxygenatom; R^(m2) represents hydrogen, methyl, fluoro, or chloro; and R^(O1)represents hydrogen; or Ar¹ represents a 5-membered heteroaryl group ofthe structure (Ar-II):

wherein Y represents CH or N; R⁷ represents —X¹—CO—R^(O1), wherein X¹represents a direct bond, (C₁₋₃)alkylene, —O—(C₁₋₃)alkylene-*,—NH—(C₁₋₃)alkylene-*, —CH═CH—, —NH—CO—*, or (C₃₋₅)cycloalkylene; whereinthe asterisks indicate the bond that is linked to the —CO—R^(O1) group;and R^(O1) represents —OH; —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);—NH—SO₂—R^(S3) wherein R^(S3) represents (C₁₋₄)alkyl, (C₃₋₆)cycloalkylwherein the (C₃₋₆)cycloalkyl optionally contains a ring oxygen atom,(C3-6)cycloalkyl-(C₁₋₃)alkylene wherein the (C₃₋₆)cycloalkyl optionallycontains a ring oxygen atom, (C₁₋₃)fluoroalkyl, or —NH₂; HET¹, whereinHET¹ represents 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl, or3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl; or HET, wherein HET representsa group selected from 1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl,2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl,2-amino-oxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl,5-methylamino-[1,3,4]thiadiazol-2-yl, 5-amino-[1,2,4]oxadiazol-3-yl; R⁶represents (C₁₋₆)alkyl; (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl;(C₁₋₃)fluoroalkoxy; halogen; (C₃₋₆)cycloalkyl; (C₃₋₆)cycloalkyl-oxy;hydroxy-(C₂₋₄)alkoxy; or —S—R^(S2) wherein R^(S2) represents(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl optionally containing one ring oxygenatom; or a pharmaceutically acceptable salt thereof.
 6. A compoundaccording to claim 5; wherein Ar¹ represents a group selected from

or a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 5; wherein the fragment

represents a group selected from benzofuranyl, benzothiophenyl,benzothiazolyl, benzoisothiazolyl, indolyl, indazolyl, naphthyl,quinolinyl, and isoquinolinyl; which group independently isunsubstituted or substituted with (R¹)_(n); wherein (R¹)_(n) representsone, two, or three substituents, wherein said substituents R¹ areindependently selected from (C₁₋₃)alkyl, (C₁₋₃)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, cyano, or amino; or a groupselected from 2,3-dihydro-benzo[b]thiophenyl, benzo[1,3]dioxolyl,1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, indanyl,5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,1,2,3,4-tetrahydro-quinolinyl; especially benzo[1,3]dioxolyl,1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl,1,2,3,4-tetrahydro-quinolinyl; which group independently isunsubstituted, or substituted with (R¹)_(n); wherein (R¹)_(n) representsone, two, or three substituents, wherein said substituents R¹ areindependently selected from (C₁₋₃)alkyl, (C₁₋₃)alkoxy, halogen,(C₁₋₃)fluoroalkyl, (C₁₋₃)fluoroalkoxy, or oxo; or a pharmaceuticallyacceptable salt thereof.
 8. A compound according to claim 6; wherein thefragment

represents a group selected from the following groups a), b), c), andd): a) benzothiophen-7-yl, benzothiophen-4-yl,2-methyl-benzothiazol-7-yl, benzofuran-7-yl, benzofuran-4-yl,2-methyl-benzofuran-7-yl, 1H-indol-7-yl, 1H-indol-4-yl,2-methyl-1H-indol-7-yl, 1-methyl-1H-indol-7-yl, 1-methyl-1H-indol-4-yl,1,2-dimethyl-1H-indol-7-yl, 1,2,3-trimethyl-1H-indol-7-yl,1,5-dimethyl-1H-indazol-4-yl; b) benzo[1,3]dioxol-4-yl,5-methoxy-benzo[1,3]dioxol-4-yl, 5-ethoxy-benzo[1,3]dioxol-4-yl,5-methoxy-2,3-dihydro-benzofuran-4-yl,6-methoxy-1-methyl-1,2,3,4-tetrahydro-quinolin-5-yl; c) naphthalen-1-yl,4-chloro-naphthalen-1-yl, 4-fluoro-naphthalen-1-yl,2-fluoro-naphthalen-1-yl, 2-bromo-naphthalen-1-yl,2-methyl-naphthalen-1-yl, 4-methyl-naphthalen-1-yl,2-amino-naphthalen-1-yl, 2,3-dimethyl-naphthalen-1-yl,2-methoxy-naphthalen-1-yl, 3-methoxy-naphthalen-1-yl,4-methoxy-naphthalen-1-yl, 2-cyano-naphthalen-1-yl,4-cyano-naphthalen-1-yl, 4-difluoromethyl-naphthalen-1-yl,2-difluoromethyl-naphthalen-1-yl, 2-ethoxy-naphthalen-1-yl,2,5-dimethoxy-naphthalen-1-yl, 2,3-dimethoxy-naphthalen-1-yl,2-n-propoxy-naphthalen-1-yl, 2-isopropoxy-naphthalen-1-yl,2-difluoromethoxy-naphthalen-1-yl; d) quinolin-8-yl,7-chloro-quinolin-8-yl, 6-methyl-quinolin-5-yl, 7-methoxy-quinolin-8-yl,6-methoxy-quinolin-5-yl, 2-methoxy-quinolin-8-yl,6-fluoro-2-methoxy-quinolin-8-yl, 5-fluoro-2-methoxy-quinolin-8-yl,7-fluoro-2-methoxy-quinolin-8-yl, 7-methoxy-4-methyl-quinolin-8-yl,6-methoxy-2-methyl-quinolin-5-yl, isoquinolin-8-yl, isoquinolin-5-yl,6-methyl-isoquinolin-5-yl; e) 6-fluoro-benzo[b]thiophen-4-yl,5-methoxy-benzo[b]thiophen-4-yl, 4-bromo-1-methyl-1H-indol-7-yl,1,5-dimethyl-1H-indol-4-yl, 5-ethoxy-benzo[b]thiophen-4-yl,6-methoxy-1-methyl-1H-indol-7-yl, 5-methoxy-1-methyl-1H-indol-4-yl; f)5-fluoro-naphthalen-1-yl, 3-fluoro-naphthalen-1-yl,4-bromo-naphthalen-1-yl, 5-methyl-naphthalen-1-yl,2-bromo-4-fluoro-naphthalen-1-yl,2-cyano-8-fluoro-5-methoxy-naphthalen-1-yl; and g) quinolin-5-yl; or apharmaceutically acceptable salt thereof.
 9. A compound according toclaim 6; wherein the fragment

represents a group selected from the following groups a), b), c), andd): a) benzothiophen-7-yl, benzothiophen-4-yl,benzofuran-7-yl2-methyl-benzofuran-7-yl, 1H-indol-4-yl,1-methyl-1H-indol-7-yl, 1-methyl-1H-indol-4-yl,1,5-dimethyl-1H-indazol-4-yl; b) 5-ethoxy-benzo[1,3]dioxol-4-yl,5-methoxy-2,3-dihydro-benzofuran-4-yl; c) naphthalen-1-yl,4-chloro-naphthalen-1-yl, 4-fluoro-naphthalen-1-yl,2-fluoro-naphthalen-1-yl, 2-bromo-naphthalen-1-yl,2-methyl-naphthalen-1-yl, 4-methyl-naphthalen-1-yl,2-amino-naphthalen-1-yl, 2,3-dimethyl-naphthalen-1-yl,2-methoxy-naphthalen-1-yl, 3-methoxy-naphthalen-1-yl,4-methoxy-naphthalen-1-yl, 2-cyano-naphthalen-1-yl,4-cyano-naphthalen-1-yl, 4-difluoromethyl-naphthalen-1-yl,2-ethoxy-naphthalen-1-yl, 2,3-dimethoxy-naphthalen-1-yl,2-n-propoxy-naphthalen-1-yl, 2-isopropoxy-naphthalen-1-yl,2-difluoromethoxy-naphthalen-1-yl; d) 6-methyl-quinolin-5-yl,6-methoxy-quinolin-5-yl, isoquinolin-5-yl; or a pharmaceuticallyacceptable salt thereof.
 10. A compound according to claim 5 selectedfrom the group consisting of:3-Ethoxy-5-{6-[2-(2-methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-methyl-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-[6-(2-naphthalen-1-yl-ethylamino)-pyrimidin-4-yl]-thiophene-2-carboxylicacid;5-{6-[2-(2-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-{6-[2-(2,3-Dimethyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-methoxy-2-methyl-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(2,3-Dimethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-{6-[2-(7-Chloro-quinolin-8-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(4-methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(4-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1-methyl-1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1-methyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(2-ethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1,2,3-trimethyl-1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(2-isopropoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(2-Difluoromethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(5-methoxy-2,3-dihydro-benzofuran-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-[6-(2-Benzofuran-7-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(2-propoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(3-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(5-methoxy-benzo[1,3]dioxol-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(5-ethoxy-benzo[1,3]dioxol-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(4-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(4-Chloro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(2-Cyano-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-{6-[2-(4-Cyano-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-{6-[2-(4-Difluoromethyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(2-methyl-benzofuran-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(2-Amino-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-{6-[2-(1,5-Dimethyl-1H-indazol-4-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-methyl-isoquinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(2-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-[6-(2-Benzo[b]thiophen-7-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;5-[6-(2-Benzo[b]thiophen-4-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;(E)-3-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acrylicacid;2-Butoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(2-Methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoicacid;{6-[3-Ethoxy-4-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-4-yl}-[2-(2-methoxy-naphthalen-1-yl)-ethyl]-amine;3-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-4H-[1,2,4]oxadiazol-5-one;3-(2-Ethoxy-4-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-1,2,4-oxadiazol-5-ol];3-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-propionicacid;N-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-oxalamicacid;3-ethoxy-5-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)-N-sulfamoylthiophene-2-carboxamide;N-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbonyl)-methanesulfonamide;3-(3-Ethoxy-5-{6-[2-(1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(5-(6-((2-(1H-indol-4-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-1,2,4-oxadiazol-5-ol;3-(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(3-Ethoxy-5-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol;3-{3-Ethoxy-5-[6-(2-quinolin-8-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one;3-(3-Ethoxy-5-(6-((2-(quinolin-8-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol;3-(3-Ethoxy-5-{6-[2-(4-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(3-Ethoxy-5-(6-((2-(4-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol;3-(3-Ethoxy-5-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(3-Ethoxy-5-(6-((2-(6-methoxyquinolin-5-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol;3-(3-Ethoxy-5-{6-[2-(1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(5-(6-((2-(1H-indol-7-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-1,2,4-oxadiazol-5-ol;3-{3-Ethoxy-5-[6-(2-isoquinolin-5-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one;3-(3-Ethoxy-5-(6-((2-(isoquinolin-5-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol;{6-[4-Ethoxy-5-(1H-tetrazol-5-yl)-thiophen-2-yl]-pyrimidin-4-yl}-[2-(6-methoxy-quinolin-5-yl)-ethyl]-amine;4-Ethoxy-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylicacid;3-(4-Ethoxy-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(4-Ethoxy-2-(6-((2-(2-methoxynaphthalen-1-yl)ethyl)amino)pyrimidin-4-yl)thiazol-5-yl)-1,2,4-oxadiazol-5-ol;5-{6-[2-(6-Methoxy-1-methyl-1,2,3,4-tetrahydro-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylicacid;3-(2-Hydroxy-ethoxy)-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclobutoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-[6-(2-naphthalen-1-yl-ethylamino)-pyrimidin-4-yl]-benzoicacid;4-{6-[2-(2-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoicacid;2-Ethoxy-4-{6-[2-(4-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclobutoxy-4-{6-[2-(2-ethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-Ethoxy-5-{6-[2-(7-methoxy-quinolin-8-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(2-methyl-1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(1,2-Dimethyl-1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;2-Cyclobutoxy-4-{6-[2-(6-methoxy-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(2-Cyano-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoicacid;5-{6-[2-(6-Methoxy-quinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylicacid;(2-Ethoxy-4-{6-[2-(6-methyl-isoquinolin-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;2-Ethoxy-4-{6-[2-(2-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclobutoxy-4-{6-[2-(2-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionicacid;2-Isobutyl-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Fluoro-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-6-propyl-benzoicacid;2-Butoxy-6-fluoro-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Difluoromethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(3-Ethoxy-5-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-aceticacid;4-Ethyl-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylicacid;2-(2-Hydroxy-ethoxy)-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;5-{6-[2-(2,5-Dimethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;2-Ethylsulfanyl-4-{6-[2-(4-methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-{3-Ethoxy-5-[6-(2-isoquinolin-8-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one;and3-(3-Ethoxy-5-(6-((2-(isoquinolin-8-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5-ol;or a pharmaceutically acceptable salt thereof.
 11. A compound accordingto claim 5 selected from the group consisting of:4-{6-[2-(4-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoicacid;5-{6-[2-(2-Cyano-8-fluoro-5-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;4-{6-[2-(6-Methoxy-1-methyl-1H-indol-7-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;4-{6-[2-(4-Bromo-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;(2-Ethoxy-4-{6-[2-(5-methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;2-Ethoxy-4-{6-[2-(5-methoxy-benzo[b]thiophen-4-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-(4-Ethyl-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(4-ethyl-2-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5-ol];4-{6-[2-(5-Methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;(2-Ethoxy-4-{6-[2-(5-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Ethoxy-4-{6-[2-(5-methoxy-1-methyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;2-Ethoxy-4-{6-[2-(5-fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-{3-Ethoxy-5-[6-(2-quinolin-5-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5-ol;3-(3-Ethoxy-5-(6-((2-(quinolin-5-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-1,2,4-oxadiazol-5(4H)-one;(2-Ethoxy-4-{6-[2-(5-methoxy-benzo[b]thiophen-4-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;4-{6-[2-(5-Fluoro-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;2-Cyclobutoxy-4-{6-[2-(1-methyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-{6-[2-(5-methyl-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(2-Ethoxy-4-{6-[2-(2-methoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;2-Ethoxy-4-{6-[2-(5-ethoxy-benzo[b]thiophen-4-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-{6-[2-(5-methoxy-1-methyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(5-Methoxy-benzo[b]thiophen-4-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;4-{6-[2-(5-Ethoxy-benzo[b]thiophen-4-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;2-Ethoxy-4-{6-[2-(2-ethoxy-naphthalen-1-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(1,5-Dimethyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid; and4-{6-[2-(5-Methoxy-1-methyl-1H-indol-4-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid; or a pharmaceutically acceptable salt thereof.
 12. Apharmaceutical composition comprising, as active principle, a compoundaccording to claim 5, or a pharmaceutically acceptable salt thereof, andat least one therapeutically inert excipient.
 13. (canceled) 14.(canceled)
 15. (canceled)
 16. (canceled)
 17. (canceled)
 18. A method ofmodulating an immune response in a subject having a tumor, comprisingadministering to a subject in need thereof an effective amount of acompound of formula (III) according to claim 5, or of a pharmaceuticallyacceptable salt thereof; wherein said effective amount reactivates theimmune system in the tumor of said subject.
 19. A method of prophylaxisor treatment of cancer; pain; endometriosis; autosomal dominantpolycystic kidney disease; acute ischemic syndromes in atheroscleroticpatients; pneumonia; and neurodegenerative diseases; or for the controlof female fertility; comprising administering to a subject in needthereof an effective amount of a compound of formula (III) according toclaim 5, or of a pharmaceutically acceptable salt thereof.
 20. A methodof prevention or treatment of a cancer selected from melanoma; lungcancer; bladder cancer; renal carcinomas; gastro-intestinal cancers;endometrial cancer; ovarian cancer; cervical cancer; and neuroblastoma;comprising administering to a subject in need thereof an effectiveamount of a compound of formula (III) according to claim 5, or of apharmaceutically acceptable salt thereof.
 21. A method of prophylaxis ortreatment of a cancer wherein said cancer is treated by modulating animmune response comprising a reactivation of the immune system in thetumor; comprising administering to a subject in need thereof aneffective amount of a compound of formula (III) according to claim 5, orof a pharmaceutically acceptable salt thereof, and optionallyadministering one or more chemotherapy agents and/or radiotherapy and/ortargeted therapy.